Thiazole derivatives

ABSTRACT

Thiazole derivatives of formula I are provided  
                 
 
as well as pharmaceutically acceptable salts and esters thereof, wherein R 1  to R 5 , a and b have the significance given in the specification. The compounds are neuropeptide Y Y5 receptor antagonists which can be used for the treatment of obesity.

BACKGROUND OF THE INVENTION

Neuropetide Y is a 36 amino acid peptide that is widely distributed inthe central and peripheral nervous systems. This peptide mediates anumber of physiological effects through its various receptor subtypes.Studies in animals have shown that neuropeptide Y is a powerful stimulusof food intake, and it has been demonstrated that activation ofneuropeptide Y Y5 receptors results in hyperphagia and decreasedthermogenesis. Therefore compounds that antagonise neuropetide Y at theY5 receptor subtype represent an approach to the treatment of eatingdisorders such as obesity and hyperphagia.

The current approach is aiming at medical intervention to induce weightloss or prevention of weight gain. This is achieved by interfering withappetite control, which is mediated by the Hypothalamus, an importantbrain region proven to control food intake. Herein, neuropeptide Y (NPY)has been proven to be one of the strongest central mediators of foodintake in several animal species. Increased NPY levels result inprofound food intake. Various receptors of neuropeptide Y (NPY) havebeen described to play a role in appetite control and weight gain.Interference with these receptors is likely to reduce appetite andconsequently weight gain. Reduction and long-term maintenance of bodyweight can also have beneficial consequences on co-associated riskfactors such as arthritis, cardiovascular diseases, diabetes and renalfailure.

SUMMARY OF THE INVENTION

The present invention provides a compound of formula (I)

wherein

-   -   R¹ is selected from the group consisting of amino, aryl,        heteroaryl, substituted aryl, and substituted heteroaryl,        wherein heteroaryl is an aromatic 5- to 10-membered ring which        has one or more hetero atoms selected from the group consisting        of nitrogen, oxygen and sulfur as ring atoms, wherein        substituted aryl is aryl substituted with from one to three        substituents, independently selected from halogen,        trifluoromethyl, trifluoromethoxy, amino, alkyl, alkoxy,        alkylcarbonyl, cyano, carbamoyl, alkoxycarbamoyl, methylendioxy,        carboxy, alkoxycarbonyl, aminocarbonyl, alkyaminocarbonyl,        dialkylaminocarbonyl, hydroxy, nitro, alkyl-SO₂—, amino-SO₂—,        and cycloalkyl, and wherein substituted heteroaryl is heteroaryl        substituted on one or more ring carbon atoms with a group        selected from the group consisting of cyano, trifluoromethyl,        trifluoromethoxy, alkyl-SO₂—, amino-SO₂—, halogen, alkoxy,        hydroxy, amino, cycloalkyl, alkylcarbonyl, aminocarbonyl nitro,        alkyl, and alkoxycarbonyl;    -   R² is hydrogen or alkyl;    -   R³ is hydrogen, alkyl or halogen;    -   R⁴ is alkyl or halogen;    -   R⁵ is hydrogen, alkyl or halogen;    -   a is zero or 1;    -   b is zero, 1 or 2;    -   or a pharmaceutically acceptable salt or ester thereof.

Compounds of the present invention are neuropeptide ligands, for exampleneuropeptide receptor antagonists and in particular, they are selectiveneuropeptide Y Y5 receptor antagonists.

DETAILED DESCRIPTION OF THE INVENTION

The present invention provides a compound of formula (I)

wherein

-   -   R₁ is selected from the group consisting of amino, aryl,        heteroaryl, substituted aryl, and substituted heteroaryl,        wherein heteroaryl is an aromatic 5- to 10-membered ring which        has one or more hetero atoms selected from the group consisting        of nitrogen, oxygen and sulfur as ring atoms, wherein        substituted aryl is aryl substituted with from one to three        substituents, independently selected from halogen,        trifluoromethyl, trifluoromethoxy, amino, alkyl, alkoxy,        alkylcarbonyl, cyano, carbamoyl, alkoxycarbamoyl, methylendioxy,        carboxy, alkoxycarbonyl, aminocarbonyl, alkyaminocarbonyl,        dialkylaminocarbonyl, hydroxy, nitro, alkyl-SO₂—, amino-SO₂—,        and cycloalkyl, and wherein substituted heteroaryl is heteroaryl        substituted on one or more ring carbon atoms with a group        selected from the group consisting of cyano, trifluoromethyl,        trifluoromethoxy, alkyl-SO₂—, amino-SO₂—, halogen, alkoxy,        hydroxy, amino, cycloalkyl, alkylcarbonyl, aminocarbonyl nitro,        alkyl, and alkoxycarbonyl;    -   R² is hydrogen or alkyl;    -   R³ is hydrogen, alxyl or halogen;    -   R⁴ is alkyl or halogen;    -   R⁵ is hydrogen, alkyl or halogen;    -   a is zero or 1;    -   b is zero, 1 or 2;    -   or a pharmaceutically acceptable salt or ester thereof.

The compounds of formula I can be used in the prophylaxis or treatmentof arthritis, cardiovascular diseases, diabetes, and renal failure, andparticularly the treatment of eating disorders and obesity.

In the present description the term “alkyl”, alone or in combination,signifies a straight-chain or branched-chain alkyl group with 1 to 8carbon atoms, preferably a straight or branched-chain alkyl group with 1to 6 carbon atoms and particularly preferred a straight orbranched-chain alkyl group with 1 to 4 carbon atoms. Examples ofstraight-chain and branched C₁-C₈ alkyl groups are methyl, ethyl,propyl, isopropyl, butyl, isobutyl, tert.-butyl, the isomeric pentyls,the isomeric hexyls, the isomeric heptyls and the isomeric octyls,preferably methyl and ethyl and most preferred methyl.

The term “cycoalkyl”, alone or in combination, signifies a cycloalkylring with 3 to 8 carbon atoms and preferably a cycloalkyl ring with 3 to6 carbon atoms, which is optionally substituted with alkyl. Examples ofC₃-C₈ cycloalkyl are cyclopropyl, methyl-cyclopropyl,dimethylcyclopropyl, cyclobutyl, methyl-cyclobutyl, cyclopentyl,methyl-cyclopentyl, cyclohexyl, methyl-cyclohexyl, dimethyl-cyclohexyl,cycloheptyl and cyclooctyl, preferably cyclopropyl.

The term “alkoxy”, alone or in combination, signifies a group of theformula alkyl-O- in which the term “alkyl” has the previously givensignificance, such as methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy,isobutoxy, sec. butoxy and tert.butoxy, preferably methoxy and ethoxyand most preferred methoxy.

The term “aryl”, alone or in combination, signifies a phenyl or naphthylgroup, preferably a phenyl group which optionally carries one or moresubstituents, preferably one to three, each independently selected fromhalogen, trifluoromethyl, trifluoromethoxy, amino, alkyl, alkoxy,alkylcarbonyl, cyano, carbamoyl, alkoxycarbamoyl, methylendioxy,carboxy, alkoxycarbonyl, aminocarbonyl, alkyaminocarbonyl,dialkylaminocarbonyl, hydroxy, nitro, alkyl-SO₂—, amino-SO₂—, cycloalkyland the like. Preferred is phenyl or naphthyl, particularly phenyloptionally substituted with one to three, preferably one or twosubstituents independently selected from alkyl, halogen, alkoxy,trifluoromethoxy, nitro and trifluoromethyl.

The term “heteroaryl”, alone or in combination, signifies aromatic 5- to10-membered heterocycle which comprises one or more, preferably one ortwo, particularly preferred one hetero atom selected from nitrogen,oxygen and sulfur, wherein nitrogen is preferred. It can be substitutedon one or more carbon atoms by cyano, trifluoromethyl, trifluoromethoxy,alkyl-SO₂—, amino-SO₂—, halogen, alkoxy, hydroxy, amino, cycloalkyl,alkylcarbonyl, aminocarbonyl nitro, alkyl, and/or alkoxycarbonyl.Preferred heteroaryl cycles are thiophenyl or pyrrolidinyl, whereinthiophenyl and pyrrolidinyl are optionally substituted with one to threesubstituents, preferably one or two independently selected from alkyl,halogen, alkoxy, trifluoromethoxy, nitro and trifluoromethyl.

The term “amino”, alone or in combination, signifies a primary,secondary or tertiary amino group bonded via the nitrogen atom, with thesecondary amino group carrying an alkyl or cycloalkyl substituent andthe tertiary amino group carrying two similar or different alkyl orcycloalkyl substituents or the two nitrogen substitutents togetherforming a ring, such as, for example, —NH₂, methylamino, ethylamino,dimethylamino, diethylamino, methyl-ethylamino, pyrrolidin-1-yl orpiperidino etc., preferably primary amino, dimethylamino anddiethylamino and particularly dimethylamino.

The term “halogen” signifies fluorine, chlorine, bromine or iodine andpreferably fluorine, chlorine or bromine.

The term “carbonyl”, alone or in combination signifies the —C(O)—group.

The term “nitro”, alone or in combination signifies the —NO₂ group.

The term “cyano”, alone or in combination signifies the group —CN.

The term “pharmaceutically acceptable salts” refers to those salts whichretain the biological effectiveness and properties of the free bases orfree acids, which are not biologically or otherwise undesirable. Thesalts are formed with inorganic acids such as hydrochloric acid,hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid and thelike, preferably hydrochloric acid, and organic acids such as aceticacid, propionic acid, glycolic acid, pyruvic acid, oxylic acid, maleicacid, malonic acid, succinic acid, fumaric acid, tartaric acid, citricacid, benzoic acid, cinnamic acid, mandelic acid, methanesulfonic acid,ethanesulfonic acid, p-toluenesulfonic acid, salicylic acid,N-acetylcystein and the like. In addition these salts may be prepared byaddition of an inorganic base or an organic base to the free acid. Saltsderived from an inorganic base include, but are not limited to, thesodium, potassium, lithium, ammonium, calcium, magnesium salts and thelike. Salts derived from organic bases include, but are not limited tosalts of primary, secondary, and tertiary amines, substituted aminesincluding naturally occurring substituted amines, cyclic amines andbasic ion exchange resins, such as isopropylamine, trimethylamine,diethylamine, triethylamine, tripropylamine, ethanolamine, lysine,arginine, N-ethylpiperidine, piperidine, polymine resins and the like.The compound of formula I can also be present in the form ofzwitterions. Particularly preferred pharmaceutically acceptable salts ofcompounds of formula I are the hydrochloride salts.

The compounds of formula I can also be solvated, e.g. hydrated. Thesolvation can be effected in the course of the manufacturing process orcan take place e.g. as a consequence of hygroscopic properties of aninitially anhydrous compound of formula I (hydration). The termpharmaceutically acceptable salts also includes physiologicallyacceptable solvates.

“Pharmaceutically acceptable esters” means that compounds of generalformula (I) may be derivatised at functional groups to providederivatives which are capable of conversion back to the parent compoundsin vivo. Examples of such compounds include physiologically acceptableand metabolically labile ester derivatives, such as methoxymethylesters, methylthiomethyl esters and pivaloyloxymethyl esters.Additionally, any physiologically acceptable equivalents of thecompounds of general formula (I), similar to the metabolically labileesters, which are capable of producing the parent compounds of generalformula (I) in vivo, are within the scope of this invention.

The term “lipase inhibitor” refers to compounds which are capable ofinhibiting the action of lipases, for example gastric and pancreaticlipases. For example orlistat and lipstatin as described in U.S. Pat.No. 4,598,089 are potent inhibitor of lipases. Lipstatin is a naturalproduct of microbial origin, and orlistat is the result of ahydrogenation of lipstatin. Other lipase inhibitors include a class ofcompound commonly referred to as panclicins. Panclicins are analogues oforlistat (Mutoh et al, 1994). The term “lipase inhibitor” refers also topolymer bound lipase inhibitors for example described in InternationalPatent Application WO99/34786 (Geltex Pharmaceuticals Inc.). Thesepolymers are characterized in that they have been substituted with oneor more groups that inhibit lipases. The term “lipase inhibitor” alsocomprises pharmaceutically acceptable salts of these compounds.

The term “lipase inhibitor” preferably refers to orlistat.

Orlistat is a known compound useful for the control or prevention ofobesity and hyperlipidemia. See, U.S. Pat. No. 4,598,089, issued Jul. 1,1986, which also discloses processes for making orlistat and U.S. Pat.No. 6,004,996, which discloses appropriate pharmaceutical compositions.Further suitable pharmaceutical compositions are described for examplein International Patent Applications WO 00/09122 and WO 00/09123.Additional processes for the preparation of orlistat are disclosed inEuropean Patent Applications Publication Nos. 185,359, 189,577, 443,449,and 524,495.

Orlistat is preferably orally administered from 60 to 720 mg per day individed doses two to three times per day. Preferred is wherein from 180to 360 mg, most preferably 360 mg per day of a lipase inhibitor isadministered to a subject, preferably in divided doses two or,particularly, three times per day. The subject is preferably an obese oroverweight human, i.e. a human with a body mass index of 25 or greater.Generally, it is preferred that the lipase inhibitor be administeredwithin about one or two hours of ingestion of a meal containing fat.Generally, for administering a lipase inhibitor as defined above it ispreferred that treatment be administered to a human who has a strongfamily history of obesity and has obtained a body mass index of 25 orgreater.

Orlistat can be administered to humans in conventional oralcompositions, such as, tablets, coated tablets, hard and soft gelatincapsules, emulsions or suspensions. Examples of carriers which can beused for tablets, coated tablets, dragees and hard gelatin capsules arelactose, other sugars and sugar alcohols like sorbitol, mannitol,maltodextrin, or other fillers; surfactants like sodium lauryle sulfate,Brij 96, or Tween 80; disintegrants like sodium starch glycolate, maizestarch or derivatives thereof; polymers like povidone, crospovidone;talc; stearic acid or its salts and the like. Suitable carriers for softgelatin capsules are, for example, vegetable oils, waxes, fats,semi-solid and liquid polyols and the like. Moreover, the pharmaceuticalpreparations can contain preserving agents, solubilizers, stabilizingagents, wetting agents, emulsifying agents, sweetening agents, coloringagents, flavoring agents, salts for varying the osmotic pressure,buffers, coating agents and antioxidants. They can also contain stillother therapeutically valuable substances. The formulations mayconveniently be presented in unit dosage form and may be prepared by anymethods known in the pharmaceutical art. Preferably, orlistat isadministered according to the formulation shown in the Examples and inU.S. Pat. No. 6,004,996, respectively.

The compounds of formula I can contain several asymmetric centers andcan be present in the form of optically pure enantiomers, mixtures ofenantiomers such as, for example, racemates, optically purediastereioisomers, mixtures of diastereoisomers, diastereoisomericracemates or mixtures of diastereoisomeric racemates.

Preferred are the compounds of formula I and pharmaceutically acceptablesalts thereof, particularly the compounds of formula I.

Further preferred are compounds according to formula I, wherein R² ishydrogen or methyl. Particularly preferred are those compounds offormula I, wherein R² is hydrogen.

Another preferred embodiment of the present invention are compounds offormula 1, wherein R³ is hydrogen or alkyl, particularly hydrogen,methyl or ethyl. Particularly preferred are those compounds according toformula I, wherein R³ is hydrogen.

Further preferred are compounds of formula I, wherein R⁴ is alkyl,particularly methyl or ethyl. Particularly preferred are those, whereinR⁴ is methyl.

Also preferred are compounds of formula I, wherein R⁵ is hydrogen oralkyl. Particularly preferred are the compounds of formula I, wherein R⁵is hydrogen.

Further preferred are the compounds of formula I, wherein b is zeroor 1. Particularly preferred are those, wherein b is zero.

Another preferred object of the present invention are the compoundsaccording to formula I, wherein a is zero. Further preferred are thosecompounds of formula I, wherein a is 1.

Preferred are the compounds according to formula I, wherein R¹ ismonoalkylamino, dialkylamino, phenyl, thiophenyl or pyrrolidinyl,wherein phenyl, thiophenyl and pyrrolidinyl are optionally substitutedwith one to three substituents independently selected from alkyl,halogen, alkoxy, trifluoromethoxy, nitro and trifluoromethyl.

Particularly preferred are the compounds according to formula I, whereinR¹ is thiophene-3-yl, 3-fluorophenyl, 4-fluorophenyl, 2-methylphenyl,2-methoxy-5-methylphenyl, dimethylamino, thiophene-2-yl,5-fluoro-2-methylphenyl, 2,4-difluorophenyl, 5-chloro-2-methoxyphenyl,2-fluorophenyl, 3-fluorophenyl, 2-chloro-5-trifluoromethylphenyl,3-nitrophenyl, 4-nitrophenyl or 4-methoxyphenyl.

Examples of preferred compounds of formula (I) are:

-   -   1. thiophene-2-sulfonic acid        {4-[5-(2-methyl-benzoyl)-thiazol-2-ylamino]-phenyl}-amide;    -   2. thiophene-3-sulfonic acid        {4-[5-(2-methyl-benzoyl)-thiazol-2-ylamino]-phenyl}-amide;    -   3. 5-chloro-thiophene-2-sulfonic acid        {4-[5-(2-methyl-benzoyl)-thiazol-2-ylamino]-phenyl}-amide;    -   4.        2-fluoro-N-{4-[5-(2-methyl-benzoyl)-thiazol-2-ylamino]-phenyl}-benzenesulfonamide;    -   5.        3-fluoro-N-{4-[5-(2-methyl-benzoyl)-thiazol-2-ylaminol-phenyl}-benzenesulfonamide;    -   6. 4-fluoro-N-{4-[5-(2-methyl-benzoyl)-thiazol-2-ylamino        -phenyl}-benzenesulfonamide;    -   7. 2,4-difluoro-N- {4-[5-(2-methyl-benzoyl)-thiazol-2-ylaminol        -phenyl}-benzenesulfonamide;    -   8. 2-methyl-N-        {4-[5-(2-methyl-benzoyl)-thiazol-2-ylamino]-phenyl}-benzenesulfonamide;    -   9.        2,5-dimethyl-N-{4-[5-(2-methyl-benzoyl)-thiazol-2-ylamino]-phenyl}-benzenesulfonamide;

10.5-fluoro-2-methyl-N-{4-[5-(2-methyl-benzoyl)-thiazol-2-ylamino]-phenyl}-benzenesulfonamide;

-   -   11.        3-methoxy-N-{4-[5-(2-methyl-benzoyl)-thiazol-2-ylamino]-phenyl}-benzenesulfonamide;    -   12.        4-methoxy-N-{4-[5-(2-methyl-benzoyl)-thiazol-2-ylamino]-phenyl}-benzenesulfonamide;    -   13.        2-methoxy-5-methyl-N-{4-[5-(2-methyl-benzoyl)-thiazol-2-ylamino]-phenyl}-benzenesulfonamide;    -   14.        2,5-dimethoxy-N-{4-[5-(2-methyl-benzoyl)-thiazol-2-ylamino]-phenyl}-benzenesulfonamide;    -   15.        5-chloro-2-methoxy-N-{4-[5-(2-methyl-benzoyl)-thiazol-2-ylamino]-phenyl}-benzenesulfonamide;    -   16.        N-{4-[5-(2-methyl-benzoyl)-thiazol-2-ylamino]-phenyl}-4-trifluoromethoxy        -benzenesulfonamide;    -   17.        N-{4-[5-(2-methyl-benzoyl)-thiazol-2-ylamino]-phenyl}-3-nitro        -benzenesulfonamide;    -   18.        2-chloro-N-{4-[5-(2-methyl-benzoyl)-thiazol-2-ylamino]-phenyl}-5-trifluoromethyl-benzenesulfonamide;    -   19.        4-chloro-N-{4-[5-(2-methyl-benzoyl)-thiazol-2-ylamino]-phenyl}-benzenesulfonamide;    -   20.        N-{4-[5-(2-methyl-benzoyl)-thiazol-2-ylamino]-phenyl}-4-nitro-benzenesulfonamide;    -   21. pyrrolidine-1-sulfonic acid        {4-[5-(2-methyl-benzoyl)-thiazol-2-ylamino]-phenyl}-amide;    -   22. dimethylamine-1-sulfonic acid        {4-[5-(2-methyl-benzoyl)-thiazol-2-ylamino]-phenyl}-amide;    -   23. thiophene-2-sulfonic acid        {3-[5-(2-methyl-benzoyl)-thiazol-2-ylamino]-phenyl}-amide;    -   24. 5-chloro-thiophene-2-sulfonic acid        {3-[5-(2-methyl-benzoyl)-thiazol-2-ylamino]-phenyl}-amide;    -   25.        3-fluoro-N-{3-[5-(2-methyl-benzoyl)-thiazol-2-ylamino]-phenyl}-benzenesulfonamide;    -   26.        4-fluoro-N-{3-[5-(2-methyl-benzoyl)-thiazol-2-ylamino]-phenyl}-benzenesulfonamide;    -   27.        2-methyl-N-{3-[5-(2-methyl-benzoyl)-thiazol-2-ylamino]-phenyl}-benzenesulfonamide;    -   28. 2,5-dimethyl-N-{3-[5-        (2-methyl-benzoyl)-thiazol-2-ylamino]-phenyl}-benzenesulfonamide;    -   29.        5-fluoro-2-methyl-N-{3-[5-(2-methyl-benzoyl)-thiazol-2-ylamino]-phenyl}-benzenesulfonamide;    -   30.        3-methoxy-N-{3-[5-(2-methyl-benzoyl)-thiazol-2-ylamino]-phenyl}-benzenesulfonamide;    -   31.        4-methoxy-N-{3-[5-(2-methyl-benzoyl)-thiazol-2-ylamino]-phenyl}-benzenesulfonamide;    -   32.        2-methoxy-5-methyl-N-{3-[5-(2-methyl-benzoyl)-thiazol-2-ylamino]-phenyl}-benzenesulfonamide;    -   33.        2-chloro-N-{3-[5-(2-methyl-benzoyl)-thiazol-2-ylamino]-phenyl}-4-trifluoromethyl-benzenesulfonamide;    -   34.        4-chloro-N-{3-[5-(2-methyl-benzoyl)-thiazol-2-ylamino]-phenyl}-benzenesulfonamide;    -   35.        N-{3-[5-(2-methyl-benzoyl)-thiazol-2-ylamino]-phenyl}-3-nitro-benzenesulfonamide;    -   36. dimethylamine-1-sulfonic acid        {3-[5-(2-methyl-benzoyl)-thiazol-2-ylamino]-phenyl}-amide;    -   37.        5-fluoro-2-methyl-N-{4-[5-(2-methyl-benzoyl)-thiazol-2-ylamino]-benzyl}-benzenesulfonamide;    -   38.        2,4-difluoro-N-{4-[5-(2-methyl-benzoyl)-thiazol-2-ylamino]-benzyl}-benzenesulfonamide;    -   39. 5-chloro-thiophene-2-sulfonic acid        4-[5-(2-methyl-benzoyl)-thiazol-2-ylamino]-benzylamide;    -   40.        5-chloro-2-methoxy-N-{4-[5-(2-methyl-benzoyl)-thiazol-2-ylamino]-benzyl}-benzenesulfonamide;    -   41.        2-chloro-N-{4-[5-(2-methyl-benzoyl)-thiazol-2-ylamino]-benzyl}-4-trifluoromethyl-benzenesulfonamide;    -   42. thiophene-3-sulfonic acid        4-[5-(2-methyl-benzoyl)-thiazol-2-ylamino]-benzylamide;    -   43.        4-fluoro-N-{4-[5-(2-methyl-benzoyl)-thiazol-2-ylamino]-benzyl}-benzenesulfonamide;    -   44.        2-fluoro-N-{4-[5-(2-methyl-benzoyl)-thiazol-2-ylamino]-benzyl}-benzenesulfonamide;    -   45.        3-fluoro-N-{4-[5-(2-methyl-benzoyl)-thiazol-2-ylamino]-benzyl}-benzenesulfonamide;    -   46.        2-chloro-N-{4-[5-(2-methyl-benzoyl)-thiazol-2-ylamino]-benzyl}-5-trifluoromethyl-benzenesulfonamide;    -   47.        N-{4-[5-(2-methyl-benzoyl)-thiazol-2-ylamino]-benzyl}-3-nitro-benzenesulfonamide;    -   48.        4-chloro-N-{4-[5-(2-methyl-benzoyl)-thiazol-2-ylamino]-benzyl}-benzenesulfonamide;    -   49.        N-{4-[5-(2-methyl-benzoyl)-thiazol-2-ylamino]-benzyl}-4-nitro-benzenesulfonamide;    -   50. dimethylamine-1-sulfonic acid        4-[5-(2-methyl-benzoyl)-thiazol-2-ylamino]-benzylamide;    -   51.        2-methyl-N-{4-[5-(2-methyl-benzoyl)-thiazol-2-ylamino]-benzyl}-benzenesulfonamide;    -   52.        2,5-dimethyl-N-{4-[5-(2-methyl-benzoyl)-thiazol-2-ylamino]-benzyl}-benzenesulfonamide;    -   53.        4-methoxy-N-{4-[5-(2-methyl-benzoyl)-thiazol-2-ylamino]-benzyl}-benzenesulfonamide;    -   54.        3-methoxy-N-{4-[5-(2-methyl-benzoyl)-thiazol-2-ylamino]-benzyl}-benzenesulfonamide;    -   55.        5-fluoro-2-methyl-N-{3-[5-(2-methyl-benzoyl)-thiazol-2-ylamino        -benzyl}-benzenesulfonamide;    -   56.        2,4-difluoro-N-{3-[5-(2-methyl-benzoyl)-thiazol-2-ylamino]-benzyl}-benzenesulfonamide;    -   57. 5-chloro-thiophene-2-sulfonic acid        3-[5-(2-methyl-benzoyl)-thiazol-2-ylamino]-benzylamide;    -   58.        5-chloro-2-methoxy-N-{3-[5-(2-methyl-benzoyl)-thiazol-2-ylamino]-benzyl}-benzenesulfonamide;    -   59.        2-chloro-N-{3-[5-(2-methyl-benzoyl)-thiazol-2-ylamino]-benzyl}-4-trifluoromethyl-benzenesulfonamide;    -   60.        2,5-dimethoxy-N-{3-[5-(2-methyl-benzoyl)-thiazol-2-ylamino]-benzyl}-benzenesulfonamide;    -   61.        3-methoxy-N-{3-[5-(2-methyl-benzoyl)-thiazol-2-ylamino]-benzyl}-benzenesulfonamide;    -   62.        2-chloro-N-{3-[5-(2-methyl-benzoyl)-thiazol-2-ylamino]-benzyl}-5-trifluoromethyl-benzenesulfonamide;    -   63.        N-{3-[5-(2-methyl-benzoyl)-thiazol-2-ylamino]-benzyl}-3-nitro-benzenesulfonamide;    -   64.        4-chloro-N-{3-[5-(2-methyl-benzoyl)-thiazol-2-ylamino]-benzyl}-benzenesulfonamide;    -   65.        N-{3-[5-(2-methyl-benzoyl)-thiazol-2-ylamino]-benzyl}-4-nitro-benzenesulfonamide;    -   66.        C-(4-fluoro-phenyl)-N-{3-[5-(2-methyl-benzoyl)-thiazol-2-ylamino]-benzyl}-methanesulfonamide;    -   67.        4-methoxy-N-{3-[5-(2-methyl-benzoyl)-thiazol-2-ylamino]-benzyl}-benzenesulfonamide;    -   68.        2,5-dimethyl-N-{3-[5-(2-methyl-benzoyl)-thiazol-2-ylamino]-benzyl}-benzenesulfonamide;    -   69. pyrrolidine-1-sulfonic acid        3-[5-(2-methyl-benzoyl)-thiazol-2-ylamino]-benzylamide;    -   70. thiophene-2-sulfonic acid        3-[5-(2-methyl-benzoyl)-thiazol-2-ylamino]-benzylamide;    -   71. thiophene-3-sulfonic acid        3-[5-(2-methyl-benzoyl)-thiazol-2-ylamino]-benzylamide;    -   72.        2-methyl-N-{3-[5-(2-methyl-benzoyl)-thiazol-2-ylamino]-benzyl}-benzenesulfonamide;    -   73.        2-fluoro-N-{3-[5-(2-methyl-benzoyl)-thiazol-2-ylamino]-benzyl}-benzenesulfonamide;        and    -   74.        3-fluoro-N-{3-[5-(2-methyl-benzoyl)-thiazol-2-ylamino]-benzyl}-benzenesulfonamide.

Examples of particularly preferred compounds of formula (I) are:

-   -   thiophene-3-sulfonic acid        {4-[5-(2-methyl-benzoyl)-thiazol-2-ylamino]-phenyl}-amide;    -   3-fluoro-N-{4-[5-(2-methyl-benzoyl)-thiazol-2-ylamino]-phenyl}-benzenesulfonamide;    -   4-fluoro-N-{4-[5-(2-methyl-benzoyl)-thiazol-2-ylamino]-phenyl}-benzenesulfonamide;    -   2-methyl-N-{4-[5-(2-methyl-benzoyl)-thiazol-2-ylamino]-phenyl}-benzenesulfonamide;    -   2-methoxy-5-methyl-N-{4-[5-(2-methyl-benzoyl)-thiazol-2-ylamino]-phenyl}-benzenesulfonamide;    -   dimethylamine-1-sulfonic acid        {4-[5-(2-methyl-benzoyl)-thiazol-2-ylamino]-phenyl}-amide;    -   thiophene-2-sulfonic acid        {3-[5-(2-methyl-benzoyl)-thiazol-2-ylamino]-phenyl}-amide;    -   5-fluoro-2-methyl-N-{4-[5-(2-methyl-benzoyl)-thiazol-2-ylamino]-benzyl}-benzenesulfonamide;    -   2,4-difluoro-N-{4-[5-(2-methyl-benzoyl)-thiazol-2-ylamino]-benzyl}-benzenesulfonamide;    -   5-chloro-2-methoxy-N-{4-[5-(2-methyl-benzoyl)-thiazol-2-ylamino]-benzyl}-benzenesulfonamide;    -   2-fluoro-N-{4-[5-(2-methyl-benzoyl)-thiazol-2-ylamino]-benzyl}-benzenesulfonamide;    -   3-fluoro-N-{4-[5-(2-methyl-benzoyl)-thiazol-2-ylamino]-benzyl}-benzenesulfonamide;    -   2-chloro-N-{4-[5-(2-methyl-benzoyl)-thiazol-2-ylamino]-benzyl}-5-trifluoromethyl        -benzenesulfonamide;    -   N-{4-[5-(2-methyl-benzoyl)-thiazol-2-ylamino]-benzyl}-3-nitro-benzenesulfonamide;    -   N-{4-[5-(2-methyl-benzoyl)-thiazol-2-ylamino]-benzyl}-4-nitro-benzenesulfonamide;    -   dimethylamine-1-sulfonic acid        4-[5-(2-methyl-benzoyl)-thiazol-2-ylamino]-benzylamide;    -   2-methyl-N-{4-[5-(2-methyl-benzoyl)-thiazol-2-ylamino]-benzyl}-benzenesulfonamide;        and    -   4-methoxy-N-{4-[5-(2-methyl-benzoyl)-thiazol-2-ylamino]-benzyl}-benzenesulfonamide.

The preparation of compounds of formula I of the present invention maybe carried out in sequential or convergent synthetic routes. Synthesesof the invention are shown in the following Schemes. The skills requiredfor carrying out the reaction and purification of the resulting productsare known to those in the art. The substituents and indices used in thefollowing description of the processes have the significance given aboveunless indicated to the contrary.

Compounds of general formula I, wherein a is zero can be preparedaccording to scheme 1 as follows:

-   -   a) Nitrothioureas IA, either commercially available or easily        synthetically available for example from the respective        nitroanilin and benzoylisothioccyanate followed by basic aqueous        work-up (reaction conditions described in literature affecting        such a reaction see for example: Tetrahedron 1963, 19, 1603),        are conveniently reacted with N,N-dimethylformamide dimethyl        acetal in the presence or the absence of a solvent. There is no        particular restriction on the nature of the solvent to be        employed, provided that it has no adverse effect on the reaction        or the reagents involved and that it can dissolve the reagents,        at least to some extent. Examples for suitable solvents include:        DMF and dioxane and the like. The reaction can take place over a        wide range of temperatures, and the precise reaction temperature        is not critical to the invention. We find it convenient to carry        out the reaction with heating from ambient temperature to        reflux. The time required for the reaction may also vary widely,        depending on many factors, notably the reaction temperature and        the nature of the reagents. However, a period of from 0.5 h to        several days will usually suffice to yield the        dimethylaminomethylene-thioureido derivatives IB. For reaction        conditions described in literature affecting such a reaction see        for example: Heterocycles 11, 313-318; 1978.    -   b) Dimethylaminomethylene-thioureido derivatives IB can be        converted to thiazole derivatives IC by reaction of IB with        a-bromoketones (a known compound or compound prepared by known        methods. The source for α-bromoketones employed is indicated as        appropriate) in a solvent such as ethanol, and the like, in the        presence or the absence of a base. There is no particular        restriction on the nature of the solvent to be employed,        provided that it has no adverse effect on the reaction or the        reagents involved and that it can dissolve the reagents, at        least to some extent. Examples for suitable solvents include:        dichloromethane, chloroform, or dioxane, methanol, ethanol and        the like. There is no particular restriction on the nature of        the base used in this stage, and any base commonly used in this        type of reaction may equally be employed here. Examples of such        bases include triethylamine and diisopropylethylamine, and the        like. The reaction can take place over a wide range of        temperatures, and the precise reaction temperature is not        critical to the invention. We find it convenient to carry out        the reaction with heating from ambient temperature to reflux.        The time required for the reaction may also vary widely,        depending on many factors, notably the reaction temperature and        the nature of the reagents. However, a period of from 0.5 h to        several days will usually suffice to yield the thiazole        derivatives IC. For reaction conditions described in literature        affecting such a reaction see for example: J. Heterocycl. Chem.,        16(7), 1377-83; 1979. The resulting compound of formula IC is a        compound of the present invention and may be the desired        product; alternatively it may be subjected to consecutive        reactions like reduction of the nitro-group by methods described        widely in literature to yield the desired thiazole derivatives        ID.    -   c) We find it convenient to reduce the nitro-group in IC with        hydrogen over Pd/C in a solvent or with SnCl₂ in a solvent.        There is no particular restriction on the nature of the solvent        to be employed, provided that it has no adverse effect on the        reaction or the reagents involved and that it can dissolve the        reagents, at least to some extent. Examples for suitable        solvents include: DMF or dioxane, methanol, ethanol and the        like. The reaction can take place over a wide range of        temperatures, and the precise reaction temperature is not        critical to the invention. We find it convenient to carry out        the reaction with heating from ambient temperature to reflux.        The time required for the reaction may also vary widely,        depending on many factors, notably the reaction temperature and        the nature of the reagents. However, a period of from 0.5 h to        several days will usually suffice to yield the amino-derivatives        ID. For reaction conditions described in literature affecting        such a reaction see for example: Tetrahedron Lett 1984, 25,        3415; J Med Chem 1983, 26, 1747. However, the resulting compound        of formula ID is a compound of the present invention and may be        the desired product; alternatively it may be subjected to        consecutive reactions.    -   d) Sulfonamides and sulfonic acid derivatives I can be prepared        from suitable starting materials according to methods known in        the art. The conversion of the amino-moiety in ID to access        sulfonamides or sulfonic acid derivatives can be affected by        methods described in literature. For example the conversion of        the amine derivatives ID or their respective salts to access        compounds of the general formula I is affected by reaction of ID        with suitable sulfonyl chlorides, or sulfamoyl chlorides        (compounds known or compound prepared by known methods)        respectively in a solvent like dichloromethane and/or MeOH and        the like and in the presence or the absence of a base. There is        no particular restriction on the nature of the solvent to be        employed, provided that it has no adverse effect on the reaction        or the reagents involved and that it can dissolve the reagents,        at least to some extent. Examples for suitable solvents include:        DCM, chloroform, MeOH or dioxane, THF, and the like. There is no        particular restriction on the nature of the base used in this        stage, and any base commonly used in this type of reaction may        equally be employed here. Examples of such bases include        triethylamine and diisopropylethylamine, and the like. The        reaction can take place over a wide range of temperatures, and        the precise reaction temperature is not critical to the        invention. We find it convenient to carry out the reaction with        heating from ambient temperature to reflux. The time required        for the reaction may also vary widely, depending on many        factors, notably the reaction temperature and the nature of the        reagents. However, a period of from 0.5 h to several days will        usually suffice to yield thiazole derivatives I. For reaction        conditions described in literature affecting such reactions see        for example: Comprehensive Organic Transformations: A Guide to        Functional Group Preparations, 2nd Edition, Richard C. Larock.        John Wiley & Sons, New York, N.Y. 1999. However, the resulting        compound of formula I (R2=H) is a compound of the present        invention and may be the desired product; alternatively it may        be subjected to consecutive reactions like alkylation of the        sulphonamide under suitable conditions. Sulfonamides I (R2=H)        are converted to sulfonamides I (R2=alkyl) by reaction of I        (R2=H) with suitable electophiles such as alkyl halogenids under        basic conditions. The reaction can be carried out in the        presence or absence of a solvent. There is no particular        restriction on the nature of the solvent to be employed,        provided that it has no adverse effect on the reaction or the        reagents involved and that it can dissolve the reagents, at        least to some extent. Examples for suitable solvents include:        chloroform, or dioxane, THF, and the like. There is no        particular restriction on the nature of the base used in this        stage, and any base commonly used in this type of reaction may        equally be employed here. Examples of such bases include NaH,        triethylamine and diisopropylethylamine, and the like. The        reaction can take place over a wide range of temperatures, and        the precise reaction temperature is not critical to the        invention. We find it convenient to carry out the reaction with        heating from ambient temperature to reflux. The time required        for the reaction may also vary widely, depending on many        factors, notably the reaction temperature and the nature of the        reagents. However, a period of from 0.5 h to several days will        usually suffice to yield thiazole derivatives I (R2=alkyl). For        reaction conditions described in literature affecting such a        reaction see for example: J Org Chem 1984, 49, 249.

Compounds of general formula I, wherein a is 1 can be prepared accordingto scheme 2 as follows:

-   -   a) Benzophenons IIA (either commercially available or        synthetically accessible via various methods described in the        art) can be formylated under various reaction conditions. We        find it convenient to formylate IIA with ethyl formate under        basic conditions in the presence or the absence of a solvent.        There is no particular restriction on the nature of the solvent        to be employed, provided that it has no adverse effect on the        reaction or the reagents involved and that it can dissolve the        reagents, at least to some extent. Examples for suitable        solvents include: MeOH, ethanol or dioxane, THF, and the like.        There is no particular restriction on the nature of the base        used in this stage, and any base commonly used in this type of        reaction may equally be employed here. Examples of such bases        include sodium methoxide, and the like. The reaction can take        place over a wide range of temperatures, and the precise        reaction temperature is not critical to the invention. We find        it convenient to carry out the reaction from 0° C. to heating to        reflux. The time required for the reaction may also vary widely,        depending on many factors, notably the reaction temperature and        the nature of the reagents. However, a period of from 0.5 h to        several days will usually suffice to yield derivatives IIB. For        reaction conditions described in literature affecting such        reactions see for example: J Am Chem Soc 1947, 69, 2942.    -   b) Compounds IIB can be brominated under various reaction        conditions described in literature. We find it convenient to        brominate IIB with Br₂ at low temperatures in a solvent to yield        derivatives IIC. There is no particular restriction on the        nature of the solvent to be employed, provided that it has no        adverse effect on the reaction or the reagents involved and that        it can dissolve the reagents, at least to some extent. Examples        for suitable solvents include: DCM, THF, and the like. The        reaction can take place over a wide range of temperatures, and        the precise reaction temperature is not critical to the        invention. We find it convenient to carry out the reaction from        −78° C. to heating to reflux. The time required for the reaction        may also vary widely, depending on many factors, notably the        reaction temperature and the nature of the reagents. However, a        period of from 0.5 h to several days will usually suffice to        yield derivatives IIC. For reaction conditions described in        literature affecting such reactions see for example: J Org Chem        1984, 49, 566.    -   c) Thioureas IID are synthetically accessible via convergent or        linear synthetic routes starting from various commercially        available starting materials. We find it convenient to react        amino-benzyl carbamic acid tert butyl esters (which are either        commercially available or easily synthetically accessible via        reaction of aminomethylanilins with Boc₂O under various reaction        conditions described in the art like for example: Bioorg Med        Chem Lett 2002, 12, 1439) with suitable electophiles such as        alkyl halogenids under basic conditions in the case that R2=H is        to be converted to R2=alkyl. The reaction can be carried out in        the presence or absence of a solvent. There is no particular        restriction on the nature of the solvent to be employed,        provided that it has no adverse effect on the reaction or the        reagents involved and that it can dissolve the reagents, at        least to some extent. Examples for suitable solvents include:        DMF, chloroform, or dioxane, THF, and the like. There is no        particular restriction on the nature of the base used in this        stage, and any base commonly used in this type of reaction may        equally be employed here. Examples of such bases include NaH,        triethylamine and diisopropylethylamine, and the like. The        reaction can take place over a wide range of temperatures, and        the precise reaction temperature is not critical to the        invention. We find it convenient to carry out the reaction with        heating from ambient temperature to reflux. The time required        for the reaction may also vary widely, depending on many        factors, notably the reaction temperature and the nature of the        reagents. However, a period of from 0.5 h to several days will        usually suffice to yield the anilinic intermediates (R2=alkyl).        For reaction conditions described in literature affecting such a        reaction see for example: Org Lett 2001, 3, 3379. Subsequent        conversion of the aniline moiety of the intermediates to the        thiourea moiety can be affected by several methods described in        the literature. However, we find it convenient to react the        intermediates with benzoylisothiocanate in a solvent and        subsequenty basic removal of the benzoyl group to liberate the        thioureas IID. For reaction conditions described in literature        affecting such a reaction see for example: Tetrahedron 1963, 19,        1603.    -   d) The reaction of IIC with IID to access the protected        precursor of IIE can be affected by various methods described in        literature. However, we find it convenient to react IIC with IID        in the presence or the absence of a solvent in the presence of a        base. There is no particular restriction on the nature of the        solvent to be employed, provided that it has no adverse effect        on the reaction or the reagents involved and that it can        dissolve the reagents, at least to some extent. Examples for        suitable solvents include: acetone, methanol and dioxane THF,        and the like. There is no particular restriction on the nature        of the base used in this stage, and any base commonly used in        this type of reaction may equally be employed here. The reaction        can take place over a wide range of temperatures, and the        precise reaction temperature is not critical to the invention.        We find it convenient to carry out the reaction with heating        from ambient temperature to reflux. The time required for the        reaction may also vary widely, depending on many factors,        notably the reaction temperature and the nature of the reagents.        However, a period of from 0.5 h to several days will usually        suffice to yield the protected precursor of IIE. However, the        resulting intermediate is a compound of the present invention        and may be the desired product; alternatively it may be        subjected to consecutive reactions like deprotection, possible        under various reaction conditions, to liberate IIE. We find it        convenient to remove the Boc-protecting group under acidic        conditions in the presence or absence of a solvent. There is no        particular restriction on the nature of the solvent to be        employed, provided that it has no adverse effect on the reaction        or the reagents involved and that it can dissolve the reagents,        at least to some extent. Examples for suitable solvents include:        dioxane, THF, and the like. There is no particular restriction        on the nature of the acid used in this stage, and any acid        commonly used in this type of reaction may equally be employed        here. Examples of such acids include HCl, TFA and the like. The        reaction can take place over a wide range of temperatures, and        the precise reaction temperature is not critical to the        invention. We find it convenient to carry out the reaction with        heating from ambient temperature to reflux. The time required        for the reaction may also vary widely, depending on many        factors, notably the reaction temperature and the nature of the        reagents. However, a period of from 0.5 h to several days will        usually suffice to yield thiazole HE or the respective salt        thereof. For reaction conditions described in literature        affecting such reactions see for example: Heterocycles 1991, 32,        1699.    -   e) Sulfonamides and sulfonic acid derivatives I can be prepared        from suitable starting materials according to methods known in        the art. The conversion of the amino-moiety in IE to access        sulfonamides or sulfonic acid derivatives can be affected by        methods described in literature. For example the conversion of        the amine derivatives HE or their respective salts to access        compounds of the general formula I is affected by reaction of        IIE with suitable sulfonyl chlorides, or sulfamoyl chlorides        (compounds known or compound prepared by known methods)        respectively in a solvent like dichloromethane and/or MeOH and        the like and in the presence or the absence of a base. There is        no particular restriction on the nature of the solvent to be        employed, provided that it has no adverse effect on the reaction        or the reagents involved and that it can dissolve the reagents,        at least to some extent. Examples for suitable solvents include:        DCM, chloroform, MeOH or dioxane, THF, and the like. There is no        particular restriction on the nature of the base used in this        stage, and any base commonly used in this type of reaction may        equally be employed here. Examples of such bases include        triethylamine and diisopropylethylamine, and the like. The        reaction can take place over a wide range of temperatures, and        the precise reaction temperature is not critical to the        invention. We find it convenient to carry out the reaction with        heating from ambient temperature to reflux. The time required        for the reaction may also vary widely, depending on many        factors, notably the reaction temperature and the nature of the        reagents. However, a period of from 0.5 h to several days will        usually suffice to yield thiazole derivatives I. For reaction        conditions described in literature affecting such reactions see        for example: Comprehensive Organic Transformations: A Guide to        Functional Group Preparations, 2nd Edition, Richard C. Larock.        John Wiley & Sons, New York, N.Y. 1999.

The conversion of a compound of formula I into a pharmaceuticallyacceptable salt can be carried out by treatment of such a compound withan inorganic acid, for example a hydrohalic acid, such as, for example,hydrochloric acid or hydrobromic acid, sulfuric acid, nitric acid,phosphoric acid etc., or with an organic acid, such as, for example,acetic acid, citric acid, maleic acid, fumaric acid, tartaric acid,methanesulfonic acid or p-toluenesulfonic acid. The correspondingcarboxylate salts can also be prepared from the compounds of formula Iby treatment with physiologically compatible bases.

The conversion of compounds of formula I into pharmaceuticallyacceptable esters or amides can be carried out e.g. by treatment ofsuited amino or hydroxyl groups present in the molecules with ancarboxylic acid such as acetic acid, with a condensating reagent such asbenzotriazol-1-yloxytris(dimethylamino]phosphonium hexafluorophosphate(BOP) or N,N-dicylohexylcarbodiimide (DCCI) to produce the carboxylicester or carboxylic amide.

A preferred process for the preparation of a compound of formula Icomprises the reaction of a compound according to formula

in the presence of a compound according to formula

in order to obtain a compound of formula I, wherein R¹ to R⁵, a and bare defined as in claim 1. Particularly preferred is the above reaction,wherein the solvent is e.g. dichloromethane and/or MeOH in the presenceor the absence of a base. Preferred bases are e.g. triethylamine anddiisopropylethylamine.

Preferred intermediates are:

-   -   [2-(4-Amino-phenylamino]-thiazol-4-yl]-o-tolyl-methanone    -   [2-(3-Amino-phenylamino]-thiazol-5-yl]-o-tolyl-methanone    -   [2-(4-Aminomethyl-phenylamino]-thiazol-5-yl]-o-tolyl-methanone;        hydrochloride    -   [2-(3-Aminomethyl-phenylamino)-thiazol-5-yl]-o-tolyl-methanone;        hydrochloride

The compounds of formula I described above for use as therapeuticallyactive substances are a further object of the invention.

Also an object of the invention are compounds described above for theproduction of medicaments for the prophylaxis and therapy of illnesseswhich are caused by disorders associated with the NPY receptor,particularly for the production of medicaments for the prophylaxis andtherapy of arthritis, cardiovascular diseases, diabetes, renal failureand particularly eating disorders and obesity.

Likewise an object of the invention are pharmaceutical compositionscontaining a compound of formula I described above and a therapeuticallyinert carrier.

An object of the invention is also the use of the compounds describedabove for the production of medicaments, particularly for the treatmentand prophylaxis of arthritis, cardiovascular diseases, diabetes, renalfailure and particularly eating disorders and obesity.

A further object of the invention comprises compounds which aremanufactured according to one of the described processes.

A further object of the invention is a method for the treatment andprophylaxis of arthritis, cardiovascular diseases, diabetes, renalfailure and particularly eating disorders and obesity whereby aneffective amount of a compound described above is administered.

According to a further aspect of the invention there is provided amethod of treatment of obesity in a human in need of such treatmentwhich comprises administration to the human a therapeutically effectiveamount of a compound according to formula I and a therapeuticallyeffective amount of a lipase inhibitor, particularly preferred, whereinthe lipase inhibitor is orlistat. Also subject of the present inventionis the mentioned method, wherein the administration is simultaneous,separate or sequential.

A further preferred embodiment of the present invention is the use of acompound of the formula I in the manufacture of a medicament for thetreatment and prevention of obesity. in a patient who is also receivingtreatment with a lipase inhibitor, particularly preferred, wherein thelipase inhibitor is orlistat.

Also an object of the invention are compounds described above for theproduction of medicaments for the prophylaxis and therapy of alcoholism.

A further object of the invention is a method for the treatment andprophylaxis of alcoholism.

Assay Procedures Cloning of Mouse NPY5 Receptor cDNAs

The full-length cDNA encoding the mouse NPY5 (mNPY5) receptor wasamplified from mouse brain cDNA using specific primers, designed basedon the published sequence, and Pfu DNA-Polymerase. The amplificationproduct was subcloned into the mammalian expression vector pcDNA3 usingEco RI and XhoI restriction sites. Positive clones were sequenced andone clone, encoding the published sequence was selected for generationof stable cell clones.

Stable Transfection

Human embryonic kidney 293 (HEK293) cells were transfected with 10 μgmNPY5 DNA using the lipofectamine reagent. Two days after transfection,geneticin selection (1 mg/ml) was initiated and several stable cloneswere isolated. One clone was further used for pharmacologicalcharacterization.

Radioligand Competition Binding

Human embryonic kidney 293 cells (HEK293), expressing recombinant mouseNPY5-receptor (mNPY5) were broken by three freeze/thawing cycles inhypotonic Tris buffer (5 mM, pH 7.4, 1 mM MgCl₂), homogenized andcentrifuged at 72,000×g for 15 min. The pellet was washed twice with 75mM Tris buffer, pH 7.4, containing 25 mM MgCl₂ and 250 mM sucrose, 0.1mM phenylmethylsulfonylfluoride and 0.1 mM 1,10-pheneanthrolin,resuspended in the same buffer and stored in aliquots at −80° C. Proteinwas determined according to the method of Lowry using bovine serumalbumine (BSA) as a standard.

Radioligand competition binding assays were performed in 250 μl 25 mMHepes buffer (pH 7.4, 2.5 mM CaCl₂, 1 mM MgCl₂, 1% bovine serumalbumine, and 0.01% NaN₃ containing 5 μg protein, 100 pM [¹²⁵I]labelledpeptide YY (PYY) and 10 μL DMSO containing increasing amounts ofunlabelled test compounds. After incubation for 1 h at 22° C., bound andfree ligand are separated by filtration over glass fibre filters. Nonspecific binding is assessed in the presence of 1 μM unlabelled PYY.Specific binding is defined as the difference between total binding andnon specific binding. IC₅₀ values are defined as the concentration ofantagonist that displaces 50% of the binding of [¹²⁵I]labelledneuropeptide Y. It is determined by linear regression analysis afterlogit/log transformation of the binding data.

Results obtained in the foregoing test using representative compounds ofthe invention as the test compounds are shown in the following table:NPY5-R (mouse) Compound IC₅₀ (nM) Example 5:3-fluoro-N-{4-[5-(2-methyl-benzoyl)- 0.74thiazol-2-ylamino]-phenyl}-benzenesulfonamide Example 23:thiophene-2-sulfonic acid {3-[5-(2- 0.54methyl-benzoyl)-thiazol-2-ylamino]-phenyl}-amide Example 37:5-fluoro-2-methyl-N-{4-[5-(2-methyl- 0.99benzoyl)-thiazol-2-ylamino]-benzyl}- benzenesulfonamide

Compounds as described above have IC₅₀ values below 1000 nM; morepreferred compounds have IC₅₀ values below 100 nM, particularly below 10nM. Most preferred compounds have IC₅₀ values below 2 nM. These resultshave been obtained by using the foregoing test.

The compounds of formula I and their pharmaceutically acceptable saltsand esters can be used as medicaments (e.g. in the form ofpharmaceutical preparations). The pharmaceutical preparations can beadministered internally, such as orally (e.g. in the form of tablets,coated tablets, dragees, hard and soft gelatin capsules, solutions,emulsions or suspensions), nasally (e.g. in the form of nasal sprays) orrectally (e.g. in the form of suppositories). However, theadministration can also be effected parentally, such as intramuscularlyor intravenously (e.g. in the form of injection solutions).

The compounds of formula I and their pharmaceutically acceptable saltsand esters can be processed with pharmaceutically inert, inorganic ororganic adjuvants for the production of tablets, coated tablets, drageesand hard gelatin capsules. Lactose, corn starch or derivatives thereof,talc, stearic acid or its salts etc. can be used, for example, as suchadjuvants for tablets, dragees and hard gelatin capsules.

Suitable adjuvants for soft gelatin capsules, are, for example,vegetable oils, waxes, fats, semi-solid substances and liquid polyols,etc.

Suitable adjuvants for the production of solutions and syrups are, forexample, water, polyols, saccharose, invert sugar, glucose, etc.

Suitable adjuvants for injection solutions are, for example, water,alcohols, polyols, glycerol, vegetable oils, etc.

Suitable adjuvants for suppositories are, for example, natural orhardened oils, waxes, fats, semi-solid or liquid polyols, etc.

Moreover, the pharmaceutical preparations can contain preservatives,solubilizers, viscosity-increasing substances, stabilizers, wettingagents, emulsifiers, sweeteners, colorants, flavorants, salts forvarying the osmotic pressure, buffers, masking agents or antioxidants.They can also contain still other therapeutically valuable substances.

In accordance with the invention the compounds of formula I and theirpharmaceutically acceptable salts can be used for the prophylaxis andtreatment of arthritis, cardiovascular diseases, diabetes, renal failureand particularly eating disorders and obesity. The dosage can vary inwide limits and will, of course, be fitted to the individualrequirements in each particular case. In general, in the case of oraladministration a daily dosage of about 0.1 mg to 20 mg per kg bodyweight, preferably about 0.5 mg to 4 mg per kg body weight (e.g. about300 mg per person), divided into preferably 1-3 individual doses, whichcan consist, for example, of the same amounts, should be appropriate. Itwill, however, be clear that the upper limit given above can be exceededwhen this is shown to be indicated.

The invention is illustrated hereinafter by Examples, which have nolimiting character.

EXAMPLES Example A Dimethylaminomethylene-3-(4-nitro-phenyl)-thiourea

A mixture of 5 g (25.3 mmol) (4-nitro-phenyl)-thiourea and 33.8 ml (253mmol) N,N-Dimethylformamide dimethyl acetal was heated to 100° C. for 1h. The precipitate was filtered off, washed with diethyl ether and driedto yield 4.74 g (74%) the title compound as orange solid.

1-H-NMR (300 MHz, DMSO d6) δ=3.13 (s, 3H, NMe₂), 3.30 (s, 3H, NMe₂),8.05 (s, br, 2H, Ar), 8.18 (d, 2H, J=9.2, Ar), 8.79 (s, 1H, PhNH), 10.95(s, 1H, N=CH-NMe₂). MS (m/e): 253.2 (MH⁺, 100%)

Example B [2-(4-Amino-phenylamino)-thiazol-4-yl]-o-tolyl-methanone

A mixture of 0.6 g (2.4 mmol)1-dimethylaminomethylene-3-(4-nitro-phenyl)-thiourea, 0.61 g (2.88 mmol)2-bromo-1-o-tolyl-ethanone (WO9907666) and 1002 ul (7.2 mmol) NEt₃ in 3ml EtOH was heated to 90° C. for 16 h. After concentration under vacuumthe mixture was treated with diluted aqueous diluted NaHCO₃ solution andextracted with ethyl acetate. The combined organic layers were filteredthrough a plug of silica topped with a layer of MgSO₄ and concentratedunder vacuum to yield 549 mg (67%) of the intermediate[2-(4-nitro-phenylamino)-thiazol-5-yl]-o-tolyl-methanone. The residuewas taken up in MeOH and hydrogenated with 1 bar H₂ over Pd/C at roomtemperature to yield after filtration and evaporation 388 mg (78%) ofthe title compound. MS (m/e): 310.2 (MH⁺, 100%)

Example 1 Thiophene-2-sulfonic acid{4-[5-(2-methyl-benzoyl)-thiazol-2-ylamino]-phenyl}-amide

A mixture of 31 mg (0.1 mmol)[2-(4-amino-phenylamino)-thiazol-4-yl]-o-tolyl-methanone and 44 ul (0.32mmol) NEt₃ in 1 ml MeOH was treated with 21.9 mg (0.12 mmol)thiophene-2-sulfonyl chloride (commercially available) in 3 ml DCM andheated to 60° C. for 16 h. After evaporation of the volatiles theresidue was taken up in 1.5 ml of MeOH/formic acid 3/2 and subjected toreversed phase HPLC purification eluting with a gradient ofacetonitrile/water. After evaporation of the product fractions 7 mg(16%) of the title compound was obtained. MS (m/e): 454.2 (MH⁻, 100%)

Examples 2 to 22 have been prepared according to the procedure describedfor the synthesis of Example 1 (see table 1).

Example C Dimethylaminomethylene-3-(3-nitro-phenyl)-thiourea

A mixture of 5 g (25.3 mmol) (4-nitro-phenyl)-thiourea and 38.2 ml (286mmol) N,N-dimethylformamide dimethyl acetal was heated to 100° C. for 1h. The precipitate was filtered off, washed wit diethyl ether and driedto yield 6.31 g (99%) the title compound as white solid. 1-H-NMR (300MHz, DMSO d6) δ=3.13 (s, 3H, NMe₂), 3.26 (s, 3H, NMe₂), 7:56 ppm (t, 2H,J=8.1, H-5), 7.89 (m br, 2H, H-4/H-6), 8.81 (s, 1H, H-2) 8.94 (s, br,1H, PhNH), 10.83 (s br, 1H, N═CH-NMe₂). MS (m/e): 253.3 (MH⁺, 100%)

Example D [2-(3-Amino-phenylamino)-thiazol-5-yl]-o-tolyl-methanone

A mixture of 0.6 g (2.4 mmol)1-dimethylaminomethylene-3-(3-nitro-phenyl)-thiourea, 0.61 g (2.88 mmol)2-bromo-1-o-tolyl-ethanone (WO9907666) and 1002 ul (7.2 mmol) NEt₃ in 3ml EtOH was heated to 90° C. for 16 h. After concentration under vacuumthe mixture was treated with diluted aqueous diluted NaHCO₃ solution andextracted with ethyl acetate. The combined organic layers were filteredthrough a plug of silica topped with a layer of MgSO₄ and concentratedin vacuo to yield 570 mg (70%) of the intermediate[2-(4-Nitro-phenylamino)-thiazol-5-yl]-o-tolyl-methanone. The residuewas taken up in H₂O/THF and reduced with SnCl₂.H20 at room temperatureduring 16 h to yield after filtration and evaporation 493 mg (95%) ofthe title compound. MS (m/e): 310.2 (MH⁺, 100%)

Example 23 Thiophene-2-sulfonic acid{3-[5-(2-methyl-benzoyl)-thiazol-2-ylamino]-phenyl}-amide

A mixture of 31 mg (0.1 mmol)[2-(3-amino-phenylamino)-thiazol-4-yl]-o-tolyl-methanone and 44 ul (0.32mmol) NEt₃ in 1 ml MeOH was treated with 21.9 mg (0.12 mmol)thiophene-2-sulfonyl chloride (commercially available) in 3 ml DCM andheated to 60° C. for 16 h. After evaporation of the volatiles theresidue was taken up in 1.5 ml of MeOH/formic acid 3/2 and subjected toreversed phase HPLC purification eluting with a gradient ofacetonitrile/water. After evaporation of the product fractions 6 mg(12%) of the title compound was yielded. MS (m/e): 454.2 (MH⁻, 100%)

Examples 24 to 36 have been prepared according to the proceduredescribed for the synthesis of Example 23 (see table 1).

Example E (4-Amino-benzyl)-carbamic Acid Tert-butyl Ester

A mixture of 7 g (57.2 mmol) 4-aminobenzylamine (commerciallyavailable), 13.7 g (63 mmol) Boc₂O and 9.57 ml (68.7 mmol) NEt₃ in 100ml aceton was further treated with 3.74 g (17.1 mmol) Boc₂O and stirredat room temperature for 16 h. After evaporation of all volatiles theresidue was extracted with ethyl acetate and the organic fractions werewashed with 0.5 N aqueous NaOH solution and dried with MgSO₄.Evaporation of the solvent yielded 12.14 (95%) of the title compound.

MS (m/e): 223.3 (MH⁺, 100%)

Example F (4-Thioureido-benzyl)-carbamic Acid Tert-butyl Ester

A mixture of 3 g (13.5 mmol) (4-Amino-benzyl)-carbamic acid tert-butylester and 1.81 ml (13.5 mmol) benzoyl isothiocyanate in 60 ml THF wasstirred at room temperature for 1 h and afterwards evaporated underreduced pressure. 80 ml MeOH and 5.6 g (40.5 mmol) potassium carbonatein 80 ml water were added and the mixture was stirred at roomtemperature for 16 h. The mixture was concentrated under reducedpressure and extracted with ethyl acetate. The organic layers werewashed with saturated NaHCO₃ solution and concentrated under reducedpressure. The residue was purified by flash column chromatography onsilica eluting with a gradient of hexane/ethyl acetate to yield afterevaporation of the product fractions 3.67 g (97%) of the title compoundas yellow amorphous solid.

1-H-NMR (300 MHz, DMSO d6) δ=1.39 (s, 9H, Boc), 4.08 (d, J=6.1 Hz, 2H,CH₂), 7.17 (d, J=8.2 Hz, 2H, H-3/H-5), 7.35 (d, J=8.2 Hz, 2H, H-2/H-6),7.36 (d, 1H, J=6.1 Hz, NHBoc), 7.38 (s, br, 2H, NH₂), 9.62 (s, 1H, NH).MS (m/e): 282.2 (MH⁺, 100%)

Example G Sodium; 3-oxo-3-o-tolyl-propen-1-olate

A suspension of 4.02 g (74.5 mmol) sodium methoxide in 200 ml diethylether was treated with 10 g (74.5 mmol) 2-methylacetophenone and 6 ml(74.5 mmol) ethyl formate under vigorous mechanical stirring at 30° C.The suspension was stirred for 3 h at 30° C. and cooled to roomtemperature. The suspension was filtered and the precipitate was washedwith diethyl ether and dried under reduced pressure to yield 8.09 g(59%) of the title compound as white solid.

1-H-NMR (300 MHz, DMSO d6) δ=2.18 (s, 3H, PhMe), 4.78 (d, J=10.1 Hz, 1H,CH), 7.07 (m, 4H, Ar), 8.50 (s, br, CH). MS (m/e): 161.0 (MH⁻, 100%)

Example H Bromo-3-hydroxy-1-o-tolyl-propenone

A solution of 8.09 g (43.9 mmol) sodium; 3-oxo-3-o-tolyl-propen-1-olatein 150 ml DCM at −78° C. was treated dropwise with 2.14 ml (41.7 mmol)Br₂ in 15 ml DCM and allowed to stirr for 2 h at −78° C. The mixture waswarmed to 0° C. and filtered. The filtrate was concentrated underreduced pressure at 5° C. to yield 7.92 g (75%) of the title compound aswhite solid. 1-H-NMR (300 MHz, DMSO d6) δ=2.18 (s, 3H, PhMe), 7.25 (m,4H, Ar), 7.74 (s, br, 1H, CH), 11.9 (s, Br, 1H, OH). MS (m/e): 240.0(MH⁻, 100%).

Example I[2-(4-Aminomethyl-phenylamino)-thiazol-5-yl]-o-tolyl-methanone;Hydrochloride

A mixture of 3.14 g (13 mmol) 2-bromo-3-hydroxy-1-o-tolyl-propenone and3.67 g (13 mmol) (4-thioureido-benzyl)-carbamic acid tert-butyl ester inacetone was stirred at 60 ° C. for 16 h. After removal of all volatilesthe residue was extracted with ethyl acetate and the organic layerswashed with saturated aqueous NaHCO₃ solution, water and brine, driedwith MgSO₄ and evaporated under reduced pressure. The residue was takenup in 150 ml dioxane and 20 ml of a 4 N HCl dioxane solution was addedand stirred at room temperature for 16 h. After addition of diethylether the precipitate was filtered off, washed with diethyl ether anddried under vacuum to yield 2.79 g (59%) of the title compound. 1-H-NMR(300 MHz, CDC1₃) δ=2.36 (s, 3H, PhMe), 4.15 (d, J=6.0 Hz, 2H, CH₂),7.2-7.8 (m, 9H, Ar+NH), 8.07 (s, 1H, H-5 thiazole), 8.8 (s, br, 2H,NH₂). MS (m/e): 324.2 (MH⁺, 100%).

Example 375-Fluoro-2-methyl-N-{4-[5-(2-methyl-benzoyl)-thiazol-2-ylamino]-benzyl}-benzenesulfonamide

A mixture of 35.8 mg (0.1mmol)[2-(4-aminomethyl-phenylamino)-thiazol-5-yl]-o-tolyl-methanone;hydrochloride, 25 mg (0.12 mmol) 5-fluoro-2-methyl-benzenesulfonylchloride (commercially available) and 69 ul (0.5 mmol) NEt₃ in 3 ml DCMwas stirred at 60 ° C. for 16 h. After evaporation of the volatiles theresidue was taken up in 1.5 ml MeOH/formic acid 2/1 and subjected toreversed phase HPLC purification eluting with a gradient ofacetonitrile/water. After evaporation of the product fractions 10 mg(21%) of the title compound was obtained.

MS (m/e): 494.1 (MH, 100%)

Examples 38 to 54 have been prepared according to the proceduredescribed for the synthesis of Example 37 (see table 1).

Example J (3-Thioureido-benzyl)-carbamic Acid Tert-butyl Ester

A mixture of3 g (13.5 mmol) (3-amino-benzyl)-carbamic acid tert-butylester (WO 9740028 Al) and 1.81 ml (13.5 mmol) benzoyl isothiocyanate in60 ml THF was stirred at room temperature for 1 h and afterwardsevaporated under reduced pressure. 80 ml MeOH and 5.6 g (40.5 mmol)potassium carbonate in 80 ml water were added and the mixture wasstirred at room temperature for 16 h. The mixture was concentrated underreduced pressure and extracted with ethyl acetate. The organic layerswere washed with saturated NaHCO₃ solution and concentrated underreduced pressure. The residue was purified by flash columnchromatography on silica eluting with a gradient of hexane/ethyl acetateto yield after evaporation of the product fractions 3.56 g (94%) of thetitle compound as yellow amorphous solid.

1-H-NMR (300 MHz, DMSO d6) δ=1.39 (s, 9H, Boc), 4.10 (d, J=6.0 Hz, 2H,CH₂), 6.9-7.4 (m, 7H, Ar+NHBoc+NH₂), 9.69 ppm (s, 1H, NH). MS (m/e):282.0 (MH⁺, 100%).

Example K[2-(3-Aminomethyl-phenylamino)-thiazol-5-yl]-o-tolyl-methanone;Hydrochloride

A mixture of 3.04 g (12.6 mmol) 2-bromo-3-hydroxy-1-o-tolyl-propenoneand 3.56 g (12.6 mmol) (4-thioureido-benzyl)-carbamic acid tert-butylester in acetone was stirred at 60° C. for 16 h. After removal of allvolatiles the residue was extracted with ethyl acetate and the organiclayers washed with saturated aqueous NaHCO₃ solution, water and brine,dried with MgSO₄ and evaporated under reduced pressure. The residue wastaken up in 150 ml dioxane and 20 ml of a 4 N HCl dioxane solution wasadded and stirred at room temperature for 16 h. After addition ofdiethyl ether the precipitate was filtered off, washed with diethylether and dried under vacuum to yield 2.81 g (62%) of the titlecompound. 1-H-NMR (300 MHz, DMSO d6) δ=2.5 (s, 3H, PhMe), 4.11 (m, br,2H, CH₂), 7.2-7.7 (m, 10 H, Ar+H-4 thiazole+NH), 8.36 (s, br, NH₂) MS(m/e): 324.2 (MH⁺, 100%)

Example 555-Fluoro-2-methyl-N-{3-[5-(2-methyl-benzoyl)-thiazol-2-ylamino]-benzyl}-benzenesulfonamide

A mixture of 35.8 mg (0.1mmol)[2-(3-aminomethyl-phenylamino)-thiazol-5-yl]-o-tolyl-methanone;hydrochloride, 25 mg (0.12 mmol) 5-fluoro-2-methyl-benzenesulfonylchloride (commercially available) and 69 ul (0.5 mmol) NEt₃ in 3 ml DCMwas stirred at 60 ° C. for 16 h. After evaporation of the volatiles theresidue was taken up in 1.5 ml MeOH/formic acid 2/1 and subjected toreversed phase HPLC purification eluting with a gradient ofacetonitrile/water. After evaporation of the product fractions 31 mg(62%) of the title compound was obtained. MS (m/e): 494.1 (MH⁻, 100%)

Examples 56 to 74 have been prepared according to the proceduredescribed for the synthesis of Example 55 (see table 1). TABLE 1 Ex MWname starting materials MW found 1 455.6 Thiophene-2-sulfonic acid[2-(4-Amino-phenylamino)- 454.2 (M − H)⁻ {4-[5-(2-methyl-thiazol-4-yl]-o-tolyl- benzoyl)-thiazol-2- methanone and Thiophene-2-ylamino]-phenyl}-amide sulfonyl chloride (commercially available) 2455.6 Thiophene-3-sulfonic [2-(4-Amino-phenylamino)- 454.2 (M − H)⁻ acid{4-[5-(2-methyl- thiazol-4-yl]-o-tolyl- benzoyl)-thiazol-2- methanoneand Thiophene-3- ylamino]-phenyl}-amide sulfonyl chloride (commerciallyavailable) 3 490 5-Chloro-thiophene-2- [2-(4-Amino-phenylamino)- 488.0(M − H)⁻ sulfonic acid {4-[5-(2- thiazol-4-yl]-o-tolyl-methyl-benzoyl)-thiazol- methanone and 5-Chloro- 2-ylamino]-phenyl}-thiophene-2-sulfonyl chloride amide (commercially available) 4 467.52-Fluoro-N-{4-[5-(2- [2-(4-Amino-phenylamino)- 466.1 (M − H)⁻methyl-benzoyl)-thiazol- thiazol-4-yl]-o-tolyl- 2-ylamino]-phenyl}-methanone and 2-Fluoro- benzenesulfonamide benzenesulfonyl chloride(commercially available) 5 467.5 3-Fluoro-N-{4-[5-(2-[2-(4-Amino-phenylamino)- 466.1 (M − H)⁻ methyl-benzoyl)-thiazol-thiazol-4-yl]-o-tolyl- 2-ylamino]-phenyl}- methanone and 3-Fluoro-benzenesulfonamide benzenesulfonyl chloride (commercially available) 6467.5 4-Fluoro-N-{4-[5-(2- [2-(4-Amino-phenylamino)- 466.1 (M − H)⁻methyl-benzoyl)-thiazol- thiazol-4-yl]-o-tolyl- 2-ylamino]-phenyl}-methanone and 2-Fluoro- benzenesulfonamide benzenesulfonyl chloride(commercially available) 7 485.5 2,4-Difluoro-N-{4-[5-(2-[2-(4-Amino-phenylamino)- 484.1 (M − H)⁻ methyl-benzoyl)-thiazol-thiazol-4-yl]-o-tolyl- 2-ylamino]-phenyl}- methanone and 2,4-Difluoro-benzenesulfonamide benzenesulfonyl chloride (commercially available) 8463.6 2-Methyl-N-{4-[5-(2- [2-(4-Amino-phenylamino)- 462.1 (M − H)⁻methyl-benzoyl)-thiazol- thiazol-4-yl]-o-tolyl- 2-ylamino]-phenyl}-methanone and 2-Methyl- benzenesulfonamide benzenesulfonyl chloride(commercially available) 9 477.6 2,5-Dimethyl-N-{4-[5-[2-(4-Amino-phenylamino)- 476.1 (M − H)⁻ (2-methyl-benzoyl)-thiazol-4-yl]-o-tolyl- thiazol-2-ylamino]- methanone and 2,5- phenyl}-Dimethyl-benzenesulfonyl benzenesulfonamide chloride (commerciallyavailable) 10 481.6 5-Fluoro-2-methyl-N-{4- [2-(4-Amino-phenylamino)-480.2 (M − H)⁻ [5-(2-methyl-benzoyl)- thiazol-4-yl]-o-tolyl-thiazol-2-ylamino]- methanone and 5-Fluoro-2- phenyl}-methyl-benzenesulfonyl benzenesulfonamide chloride (commerciallyavailable) 11 479.6 3-Methoxy-N-{4-[5-(2- [2-(4-Amino-phenylamino)-478.1 (M − H)⁻ methyl-benzoyl)-thiazol- thiazol-4-yl]-o-tolyl-2-ylamino]-phenyl}- methanone and 3-Methoxy- benzenesulfonamidebenzenesulfonyl chloride (commercially available) 12 479.64-Methoxy-N-{4-[5-(2- [2-(4-Amino-phenylamino)- 478.1 (M − H)⁻methyl-benzoyl)-thiazol- thiazol-4-yl]-o-tolyl- 2-ylamino]-phenyl}-methanone and 4-Methoxy- benzenesulfonamide benzenesulfonyl chloride(commercially available) 13 493.6 2-Methoxy-5-methyl-N-[2-(4-Amino-phenylamino)- 492.1 (M − H)⁻ {4-[5-(2-methyl-thiazol-4-yl]-o-tolyl- benzoyl)-thiazol-2- methanone and 2-Methoxy-ylamino]-phenyl}- 5-methyl-benzenesulfonyl benzenesulfonamide chloride(commercially available) 14 509.6 2,5-Dimethoxy-N-{4-[5-[2-(4-Amino-phenylamino)- 508.2 (M − H)⁻ (2-methyl-benzoyl)-thiazol-4-yl]-o-tolyl- thiazol-2-ylamino]- methanone and phenyl}-2,5Dimethoxy- benzenesulfonamide benzenesulfonyl chloride (commerciallyavailable) 15 514 5-Chloro-2-methoxy-N- [2-(4-Amino-phenylamino)- 512.0(M − H)⁻ {4-[5-(2-methyl- thiazol-4-yl]-o-tolyl- benzoyl)-thiazol-2-methanone and 5-Chloro-2- ylamino]-phenyl}- methoxy-benzenesulfonylbenzenesulfonamide chloride (commercially available) 16 533.5N-{4-[5-(2-Methyl- [2-(4-Amino-phenylamino)- 532.0 (M − H)⁻benzoyl)-thiazol-2- thiazol-4-yl]-o-tolyl- ylamino]-phenyl}-4- methanoneand 4- trifluoromethoxy- Trifluoromethoxy- benzenesulfonamidebenzenesulfonyl chloride (commercially available) 17 494.6N-{4-[5-(2-Methyl- [2-(4-Amino-phenylamino)- 493.1 (M − H)⁻benzoyl)-thiazol-2- thiazol-4-yl]-o-tolyl- ylamino]-phenyl}-3-nitro-methanone and 3-Nitro- benzenesulfonamide benzenesulfonyl chloride(commercially available) 18 552 2-Chloro-N-{4-[5-(2-[2-(4-Amino-phenylamino)- 549.9 (M − H)⁻ methyl-benzoyl)-thiazol-thiazol-4-yl]-o-tolyl- 2-ylamino]-phenyl}-5- methanone and 2-Chloro-5-trifluoromethyl- trifluoromethyl- benzenesulfonamide benzenesulfonylchloride (commercially available) 19 484 4-Chloro-N-{4-[5-(2-[2-(4-Amino-phenylamino)- 482.2 (M − H)⁻ methyl-benzoyl)-thiazol-thiazol-4-yl]-o-tolyl- 2-ylamino]-phenyl}- methanone and 4-Chloro-benzenesulfonamide benzenesulfonyl chloride (commercially available) 20494.6 N-{4-[5-(2-Methyl- [2-(4-Amino-phenylamino)- 493.1 (M − H)⁻benzoyl)-thiazol-2- thiazol-4-yl]-o-tolyl- ylamino]-phenyl}-4- methanoneand 4-Nitro- nitro- benzenesulfonyl chloride benzenesulfonamide(commercially available) 21 442.6 Pyrrolidine-1-sulfonic[2-(4-Amino-phenylamino)- 441.2 (M − H)⁻ acid {4-[5-(2-methyl-thiazol-4-yl]-o-tolyl- benzoyl)-thiazol-2- methanone and Pyrrolidine-ylamino]-phenyl}-amide 1-sulfonyl chloride (commercially available) 22416.5 Dimethylamine-1- [2-(4-Amino-phenylamino)- 415.2 (M − H)⁻ sulfonicacid {4-[5-(2- thiazol-4-yl]-o-tolyl- methyl-benzoyl)-thiazol- methanoneand 2-ylamino]-phenyl}- Dimethylamine-1-sulfonyl amide chloride(commercially available) 23 455.6 Thiophene-2-sulfonic[2-(3-Amino-phenylamino)- 454.2 (M − H)⁻ acid {3-[5-(2-methyl-thiazol-4-yl]-o-tolyl- benzoyl)-thiazol-2- methanone and Thiophene-2-ylamino]-phenyl}-amide sulfonyl chloride (commercially available) 24 4905-Chloro-thiophene-2- [2-(3-Amino-phenylamino)- 488.0 (M − H)⁻ sulfonicacid {3-[5-(2- thiazol-4-yl]-o-tolyl- methyl-benzoyl)-thiazol- methanoneand 5-Chloro- 2-ylamino]-phenyl}- thiophene-2-sulfonyl chloride amide(commercially available) 25 467.5 3-Fluoro-N-{3-[5-(2-[2-(3-Amino-phenylamino)- 466.1 (M − H)⁻ methyl-benzoyl)-thiazol-thiazol-4-yl]-o-tolyl- 2-ylamino]-phenyl}- methanone and 3-Fluoro-benzenesulfonamide benzenesulfonyl chloride (commercially available) 26467.5 4-Fluoro-N-{3-[5-(2- [2-(3-Amino-phenylamino)- 466.1 (M − H)⁻methyl-benzoyl)-thiazol- thiazol-4-yl]-o-tolyl- 2-ylamino]-phenyl}-methanone and 4-Fluoro- benzenesulfonamide benzenesulfonyl chloride(commercially available) 27 463.6 2-Methyl-N-{3-[5-(2-[2-(3-Amino-phenylamino)- 462.2 (M − H)⁻ methyl-benzoyl)-thiazol-thiazol-4-yl]-o-tolyl- 2-ylamino]-phenyl}- methanone and 2-Methyl-benzenesulfonamide benzenesulfonyl chloride (commercially available) 28477.6 2,5-Dimethyl-N-{3-[5- [2-(3-Amino-phenylamino)- 476.1 (M − H)⁻(2-methyl-benzoyl)- thiazol-4-yl]-o-tolyl- thiazol-2-ylamino]- methanoneand 2,5- phenyl}- Dimethyl-benzenesulfonyl benzenesulfonamide chloride(commercially available) 29 481.6 5-Fluoro-2-methyl-N-{3-[2-(3-Amino-phenylamino)- 480.2 (M − H)⁻ [5-(2-methyl-benzoyl)-thiazol-4-yl]-o-tolyl- thiazol-2-ylamino]- methanone and 5-Fluoro-2-phenyl}- methyl-benzenesulfonyl benzenesulfonamide chloride(commercially available) 30 479.6 3-Methoxy-N-{3-[5-(2-[2-(3-Amino-phenylamino)- 478.1 (M − H)⁻ methyl-benzoyl)-thiazol-thiazol-4-yl]-o-tolyl- 2-ylamino]-phenyl}- methanone and 3-Methoxy-benzenesulfonamide benzenesulfonyl chloride (commercially available) 31479.6 4-Methoxy-N-{3-[5-(2- [2-(3-Amino-phenylamino)- 478.1 (M − H)⁻methyl-benzoyl)-thiazol- thiazol-4-yl]-o-tolyl- 2-ylamino]-phenyl}-methanone and 3-Methoxy- benzenesulfonamide benzenesulfonyl chloride(commercially available) 32 493.6 2-Methoxy-5-methyl-N-[2-(3-Amino-phenylamino)- 492.1 (M − H)⁻ {3-[5-(2-methyl-thiazol-4-yl]-o-tolyl benzoyl)-thiazol-2- methanone and 2-Methoxy-ylamino]-phenyl}- 5-methyl-benzenesulfonyl benzenesulfonamide chloride(commercially available) 33 552 2-Chloro-N-{3-[5-(2-[2-(3-Amino-phenylamino)- 549.9 (M − H)⁻ methyl-benzoyl)-thiazol-thiazol-4-yl]-o-tolyl- 2-ylamino]-phenyl}-4- methanone and 2-Chloro-4-trifluoromethyl- trifluoromethyl- benzenesulfonamide benzenesulfonylchloride (commercially available) 34 484 4-Chloro-N-{3-[5-(2-[2-(3-Amino-phenylamino)- 482.1 (M − H)⁻ methyl-benzoyl)-thiazol-thiazol-4-yl]-o-tolyl- 2-ylamino]-phenyl}- methanone and 4-Chloro-benzenesulfonamide benzenesulfonyl chloride (commercially available) 35494.6 N-{3-[5-(2-Methyl- [2-(3-Amino-phenylamino)- 493.0 (M − H)⁻benzoyl)-thiazol-2- thiazol-4-yl]-o-tolyl- ylamino]-phenyl}-3- methanoneand 3-Nitro- nitro- benzenesulfonyl chloride benzenesulfonamide(commercially available) 36 416.5 Dimethylamine-1-[2-(3-Amino-phenylamino)- 415.1 (M − H)⁻ sulfonic acid {3-[5-(2-thiazol-4-yl]-o-tolyl- methyl-benzoyl)-thiazol- methanone and2-ylamino]-phenyl}- Dimethylamine-1-sulfonyl amide chloride(commercially available) 37 495.6 5-Fluoro-2-methyl-N-{4-[2-(4-Aminomethyl- 494.1 (M − H)⁻ [5-(2-methyl-benzoyl)-phenylamino)-thiazol-5-yl]- thiazol-2-ylamino]- o-tolyl-methanone;benzyl}- hydrochloride and 5-Fluoro- benzenesulfonamide2-methyl-benzenesulfonyl chloride (commercially available) 38 499.62,4-Difluoro-N-{4-[5-(2- [2-(4-Aminomethyl- 498.0 (M − H)⁻methyl-benzoyl)-thiazol- phenylamino)-thiazol-5-yl]- 2-ylamino]-benzyl}-o-tolyl-methanone; benzenesulfonamide hydrochloride and 2,4-Difluoro-benzenesulfonyl chloride (commercially available) 39 504.15-Chloro-thiophene-2- [2-(4-Aminomethyl- 502.0 (M − H)⁻ sulfonic acid4-[5-(2- phenylamino)-thiazol-5-yl]- methyl-benzoyl)-thiazol-o-tolyl-methanone; 2-ylamino]-benzylamide hydrochloride and 5-Chloro-thiophene-2-sulfonyl chloride (commercially available) 40 528.15-Chloro-2-methoxy-N- [2-(4-Aminomethyl- 526.0 (M − H)⁻ {4-[5-(2-methyl-phenylamino)-thiazol-5-yl]- benzoyl)-thiazol-2- o-tolyl-methanone;ylamino]-benzyl}- hydrochloride and 5-Chloro- benzenesulfonamide2-methoxy-benzenesulfonyl chloride (commercially available) 41 5662-Chloro-N-{4-[5-(2- [2-(4-Aminomethyl- 564.1 (M − H)⁻methyl-benzoyl)-thiazol- phenylamino)-thiazol-5-yl]-2-ylamino]-benzyl}-4- o-tolyl-methanone; trifluoromethyl- hydrochlorideand 2-Chloro- benzenesulfonamide 4-trifluoromethyl- benzenesulfonylchloride (commercially available) 42 469.6 Thiophene-3-sulfonic acid[2-(4-Aminomethyl- 468.0 (M − H)⁻ 4-[5-(2-methyl-phenylamino)-thiazol-5-yl]- benzoyl)-thiazol-2- o-tolyl-methanone;ylamino]-benzylamide hydrochloride and Thiophene-3-sulfonyl chloride(commercially available) 43 481.6 4-Fluoro-N-{4-[5-(2-[2-(4-Aminomethyl- 480.2 (M − H)⁻ methyl-benzoyl)-thiazol-phenylamino)-thiazol-5-yl]- 2-ylamino]-benzyl}- o-tolyl-methanone;benzenesulfonamide hydrochloride and 4-Fluoro- benzenesulfonyl chloride(commercially available) 44 481.6 2-Fluoro-N-{4-[5-(2-[2-(4-Aminomethyl- 480.2 (M − H)⁻ methyl-benzoyl)-thiazol-phenylamino)-thiazol-5-yl]- 2-ylamino]-benzyl}- o-tolyl-methanone;benzenesulfonamide hydrochloride and 2-Fluoro- benzenesulfonyl chloride(commercially available) 45 481.6 3-Fluoro-N-{4-[5-(2-[2-(4-Aminomethyl- 480.2 (M − H)⁻ methyl-benzoyl)-thiazol-phenylamino)-thiazol-5-yl]- 2-ylamino]-benzyl}- o-tolyl-methanone;benzenesulfonamide hydrochloride and 3-Fluoro- benzenesulfonyl chloride(commercially available) 46 566 2-Chloro-N-{4-[5-(2- [2-(4-Aminomethyl-564.2 (M − H)⁻ methyl-benzoyl)-thiazol- phenylamino)-thiazol-5-yl]-2-ylamino]-benzyl}-5- o-tolyl-methanone; trifluoromethyl- hydrochlorideand 2-Chloro- benzenesulfonamide 5-trifluoromethyl- benzenesulfonylchloride (commercially available) 47 508.6 N-{4-[5-(2-Methyl-[2-(4-Aminomethyl- 507.2 (M − H)⁻ benzoyl)-thiazol-2-phenylamino)-thiazol-5-yl]- ylamino]-benzyl}-3- o-tolyl-methanone;nitro- hydrochloride and 3-Nitro- benzenesulfonamide benzenesulfonylchloride (commercially available) 48 498 4-Chloro-N-{4-[5-(2-[2-(4-Aminomethyl- 496.0 (M − H)⁻ methyl-benzoyl)-thiazol-phenylamino)-thiazol-5-yl]- 2-ylamino]-benzyl}- o-tolyl-methanone;benzenesulfonamide hydrochloride and 4-Chloro- benzenesulfonyl chloride(commercially available) 49 508.6 N-{4-[5-(2-Methyl- [2-(4-Aminomethyl-507.2 (M − H)⁻ benzoyl)-thiazol-2- phenylamino)-thiazol-5-yl]-ylamino]-benzyl}-4- o-tolyl-methanone; nitro- hydrochloride and 4-Nitro-benzenesulfonamide benzenesulfonyl chloride (commercially available) 50430.6 Dimethylamine-1- [2-(4-Aminomethyl- 429.3 (M − H)⁻ sulfonic acid4-[5-(2 phenylamino)-thiazol-5-yl]- methyl-benzoyl)-thiazol-o-tolyl-methanone; 2-ylamino]-benzylamide hydrochloride andDimethylamine-1-sulfonyl chloride (commercially available) 51 477.62-Methyl-N-{4-[5-(2- [2-(4-Aminomethyl- 476.1 (M − H)⁻methyl-benzoyl)-thiazol- phenylamino)-thiazol-5-yl]- 2-ylamino]-benzyl}-o-tolyl-methanone; benzenesulfonamide hydrochloride and 2-Methyl-benzenesulfonyl chloride (commercially available) 52 491.62,5-Dimethyl-N-{4-[5- [2-(4-Aminomethyl- 490.2 (M − H)⁻(2-methyl-benzoyl)- phenylamino)-thiazol-5-yl]- thiazol-2-ylamino]-o-tolyl-methanone; benzyl}- hydrochloride and 2,5- benzenesulfonamideDimethyl-benzenesulfonyl chloride (commercially available) 53 493.64-Methoxy-N-{4-[5-(2- [2-(4-Aminomethyl- 492.1 (M − H)⁻methyl-benzoyl)-thiazol- phenylamino)-thiazol-5-yl]- 2-ylamino]-benzyl}-o-tolyl-methanone; benzenesulfonamide hydrochloride and 4-Methoxy-benzenesulfonyl chloride (commercially available) 54 493.63-Methoxy-N-{4-[5-(2- [2-(4-Aminomethyl- 492.1 (M − H)⁻methyl-benzoyl)-thiazol- phenylamino)-thiazol-5-yl]- 2-ylamino]-benzyl}-o-tolyl-methanone; benzenesulfonamide hydrochloride and 3-Methoxy-benzenesulfonyl chloride (commercially available) 55 495.65-Fluoro-2-methyl-N-{3- [2-(3-Aminomethyl- 494.1 (M − H)⁻[5-(2-methyl-benzoyl)- phenylamino)-thiazol-5-yl]- thiazol-2-ylamino]-o-tolyl-methanone; benzyl}- hydrochloride and 5-Fluoro-benzenesulfonamide 2-Methyl-benzenesulfonyl chloride (commerciallyavailable) 56 499.6 2,4-Difluoro-N-{3-[5-(2- [2-(3-Aminomethyl- 498.0 (M− H)⁻ methyl-benzoyl)-thiazol- phenylamino)-thiazol-5-yl]-2-ylamino]-benzyl}- o-tolyl-methanone; benzenesulfonamide hydrochlorideand 2,4- Difluoro-benzenesulfonyl chloride (commercially available) 57504.1 5-Chloro-thiophene-2- [2-(3-Aminomethyl- 502.0 (M − H)⁻ sulfonicacid 3-[5-(2- phenylamino)-thiazol-5-yl]- methyl-benzoyl)-thiazol-o-tolyl-methanone; 2-ylamino]-benzylamide hydrochloride and 5-Chloro-thiophene-2-sulfonyl chloride (commercially available) 58 528.15-Chloro-2-methoxy-N- [2-(3-Aminomethyl- 526.0 (M − H)⁻ {3-[5-(2-methyl-phenylamino)-thiazol-5-yl]- benzoyl)-thiazol-2- o-tolyl-methanone;ylamino]-benzyl}- hydrochloride and 5-Chloro- benzenesulfonamide2-methoxy-benzenesulfonyl chloride (commercially available) 59 5662-Chloro-N-{3-[5-(2- [2-(3-Aminomethyl- 564.2 (M − H)⁻methyl-benzoyl)-thiazol- phenylamino)-thiazol-5-yl]-2-ylamino]-benzyl}-4- o-tolyl-methanone; trifluoromethyl- hydrochlorideand 2-Chloro- benzenesulfonamide 4-trifluoromethyl- benzenesulfonylchloride (commercially available) 60 523.6 2,5-Dimethoxy-N-{3-[5-[2-(3-Aminomethyl- 522.1 (M − H)⁻ (2-methyl-benzoyl)-phenylamino)-thiazol-5-yl]- thiazol-2-ylamino]- o-tolyl-methanone;benzyl}- hydrochloride and 2,5- benzenesulfonamideDimethoxy-benzenesulfonyl chloride (commercially available) 61 493.63-Methoxy-N-{3-[5-(2- [2-(3-Aminomethyl- 492.1 (M − H)⁻methyl-benzoyl)-thiazol phenylamino)-thiazol-5-yl]- 2-ylamino]-benzyl}-o-tolyl-methanone; benzenesulfonamide hydrochloride and 3-Methoxy-benzenesulfonyl chloride (commercially available) 62 5662-Chloro-N-{3-[5-(2- [2-(3-Aminomethyl- 564.1 (M − H)⁻methyl-benzoyl)-thiazol- phenylamino)-thiazol-5-yl]-2-ylamino]-benzyl}-5- o-tolyl-methanone; trifluoromethyl- hydrochlorideand 2-Chloro- benzenesulfonamide 5-trifluoromethyl- benzenesulfonylchloride (commercially available) 63 508.6 N-{3-[5-(2-Methyl-[2-(3-Aminomethyl- 507.2 (M − H)⁻ benzoyl)-thiazol-2-phenylamino)-thiazol-5-yl]- ylamino]-benzyl}-3- o-tolyl-methanone;nitro- hydrochloride and 3-Nitro- benzenesulfonamide benzenesulfonylchloride (commercially available) 64 498 4-Chloro-N-{3-[5-(2-[2-(3-Aminomethyl- 496.1 (M − H)⁻ methyl-benzoyl)-thiazol-phenylamino)-thiazol-5-yl]- 2-ylamino]-benzyl}- o-tolyl-methanone;benzenesulfonamide hydrochloride and 4-Chloro- benzenesulfonyl chloride(commercially available) 65 508.6 N-{3-[5-(2-Methyl- [2-(3-Aminomethyl-507.2 (M − H)⁻ benzoyl)-thiazol-2- phenylamino)-thiazol-5-yl]-ylamino]-benzyl}-4- o-tolyl-methanone; nitro- hydrochloride and 4-Nitro-benzenesulfonamide benzenesulfonyl chloride (commercially available) 66495.6 C-(4-Fluoro-phenyl)-N- [2-(3-Aminomethyl- 494.1 (M − H)⁻{3-[5-(2-methyl- phenylamino)-thiazol-5-yl]- benzoyl)-thiazol-2-o-tolyl-methanone; ylamino]-benzyl}- hydrochloride and (4-Fluoro-methanesulfonamide phenyl)-methanesulfonyl chloride (commerciallyavailable) 67 493.6 4-Methoxy-N-{3-[5-(2- [2-(3-Aminomethyl- 492.1 (M −H)⁻ methyl-benzoyl)-thiazol- phenylamino)-thiazol-5-yl]-2-ylamino]-benzyl}- o-tolyl-methanone; benzenesulfonamide hydrochlorideand 4- Methoxy-benzenesulfonyl chloride (commercially available) 68491.6 2,5-Dimethyl-N-{3-[5- [2-(3-Aminomethyl- 490.2 (M − H)⁻(2-methyl-benzoyl)- phenylamino)-thiazol-5-yl]- thiazol-2-ylamino]-o-tolyl-methanone; benzyl}- hydrochloride and 2,5- benzenesulfonamideDimethyl-benzenesulfonyl chloride (commercially available) 69 456.6Pyrrolidine-1-sulfonic acid [2-(3-Aminomethyl- 455.3 (M − H)⁻3-[5-(2-methyl- phenylamino)-thiazol-5-yl]- benzoyl)-thiazol-2-o-tolyl-methanone; ylamino]-benzylamide hydrochloride andPyrrolidin-1-sulfonyl chloride (commercially available) 70 469.6Thiophene-2-sulfonic acid [2-(3-Aminomethyl- 468.0 (M − H)⁻3-[5-(2-methyl- phenylamino)-thiazol-5-yl]- benzoyl)-thiazol-2-o-tolyl-methanone; ylamino]-benzylamide hydrochloride andThiophene-2-sulfonyl chloride (commercially available) 71 469.6Thiophene-3-sulfonic [2-(3-Aminomethyl- 468.0 (M − H)⁻ acid3-[5-(2-methyl- phenylamino)-thiazol-5-yl]- benzoyl)-thiazol-2-o-tolyl-methanone; ylamino]-benzylamide hydrochloride andThiophene-3-sulfonyl chloride (commercially available) 72 477.62-Methyl-N-{3-[5-(2- [2-(3-Aminomethyl- 476.1 (M − H)⁻methyl-benzoyl)-thiazol- phenylamino)-thiazol-5-yl]- 2-ylamino]-benzyl}-o-tolyl-methanone; benzenesulfonamide hydrochloride and 2-Methyl-benzenesulfonyl chloride (commercially available) 73 481.62-Fluoro-N-{3-[5-(2- [2-(3-Aminomethyl- 480.2 (M − H)⁻methyl-benzoyl)-thiazol- phenylamino)-thiazol-5-yl]- 2-ylamino]-benzyl}-o-tolyl-methanone; benzenesulfonamide hydrochloride and 2-Fluoro-benzenesulfonyl chloride (commercially available) 74 481.63-Fluoro-N-{3-[5-(2- [2-(3-Aminomethyl- 480.2 (M − H)⁻methyl-benzoyl)-thiazol- phenylamino)-thiazol-5-yl]- 2-ylamino]-benzyl}-o-tolyl-methanone; benzenesulfonamide hydrochloride and 3-Fluoro-benzenesulfonyl chloride (commercially available)

Example A

A compound of formula I can be used in a manner known per se as theactive ingredient for the production of tablets of the followingcomposition: Per tablet Active ingredient 200 mg Microcrystallinecellulose 155 mg Corn starch  25 mg Talc  25 mgHydroxypropylmethylcellulose  20 mg 425 mg

Example B

A compound of formula I can be used in a manner known per se as theactive ingredient for the production of capsules of the followingcomposition: Per capsule Active ingredient 100.0 mg Corn starch  20.0 mgLactose  95.0 mg Talc  4.5 mg Magnesium stearate  0.5 mg 220.0 mg

1. A compound of formula I:

wherein R¹ is selected from the group consisting of amino, aryl,heteroaryl, substituted aryl, and substituted heteroaryl, whereinheteroaryl is an aromatic 5- to 10-membered ring which has one or morehetero atoms selected from the group consisting of nitrogen, oxygen andsulfur as ring atoms, wherein substituted aryl is aryl substituted withfrom one to three substituents, independently selected from halogen,trifluoromethyl, trifluoromethoxy, amino, alkyl, alkoxy, alkylcarbonyl,cyano, carbamoyl, alkoxycarbamoyl, methylendioxy, carboxy,alkoxycarbonyl, aminocarbonyl, alkyaminocarbonyl, dialkylaminocarbonyl,hydroxy, nitro, alkyl-SO₂—, amino-SO₂—, and cydoalkyl, and whereinsubstituted heteroaryl is heteroaryl substituted on one or more ringcarbon atoms with a group selected from the group consisting of cyano,trifluoromethyl, trifluoromethoxy, alkyl-SO₂—, amino-SO₂—, halogen,alkoxy, hydroxy, amino, cycloalkyl, alkylcarbonyl, aminocarbonyl nitro,alkyl, and alkoxycarbonyl; R² is hydrogen or alkyl; R³ is hydrogen,alkyl or halogen; R⁴ is alkyl or halogen; R⁵ is hydrogen, alkyl orhalogen; a is zero or 1; b is zero, 1 or 2; or a pharmaceuticallyacceptable salt or ester thereof.
 2. The compound according to claim 1,wherein R² is hydrogen.
 3. The compound according to claim 1, wherein R³is hydrogen.
 4. The compound according to claim 1, wherein R⁴ is alkyl.5. The compound according to claim 4, wherein R⁴ is methyl.
 6. Thecompound according to claim 1, wherein R⁵ is hydrogen.
 7. The compoundaccording to claim 1, wherein b is zero.
 8. The compound according toclaim 1, wherein a is zero.
 9. The compound according to claim 1,wherein a is
 1. 10. The compound according to claim 1, wherein R¹ isselected from the group consisting of monoalkylamino, dialkylamino,phenyl, thiophenyl, pyrrolidinyl, substituted phenyl, substitutedthiophenyl, and substituted pyrrolidinyl, wherein substituted phenyl,substituted thiophenyl and substituted pyrrolidinyl are phenyl,thiophenyl and pyrrolidynlyl, respectively, substituted with one tothree substituents independently selected from the group consisting ofalkyl, halogen, alkoxy, trifluoromethoxy, nitro and trifluoromethyl. 11.The compound according to claim 10, wherein R¹ is selected from thegroup consisting of thiophene-3-yl, 3-fluorophenyl, 4-fluorophenyl,2-methylphenyl, 2-methoxy-5-methylphenyl, dimethylamino, thiophene-2-yl,5-fluoro-2-methylphenyl, 2,4-difluorophenyl, 5-chloro-2-methoxyphenyl,2-fluorophenyl, 3-fluorophenyl, 2-chloro-5-trifluoromethylphenyl,3-nitrophenyl, 4-nitrophenyl and 4-methoxyphenyl.
 12. The compoundaccording to claim 1, selected from the group consisting of:thiophene-2-sulfonic acid{4-[5-(2-methyl-benzoyl)-thiazol-2-ylamino]-phenyl}-amide;thiophene-3-sulfonic acid{4-[5-(2-methyl-benzoyl)-thiazol-2-ylamino]-phenyl}-amide; and5-chloro-thiophene-2-sulfonic acid{4-[5-(2-methyl-benzoyl)-thiazol-2-ylamino]-phenyl}-amide; or apharmaceutically acceptable salt or ester thereof.
 13. The compoundaccording to claim 1, selected from the group consisting of:2-fluoro-N-{4-[5-(2-methyl-benzoyl)-thiazol-2-ylamino]-phenyl}-benzenesulfonamide;3-fluoro-N-{4-[5-(2-methyl-benzoyl)-thiazol-2-ylamino]-phenyl}-benzenesulfonamide;4-fluoro-N-{4-[5-(2-methyl-benzoyl)-thiazol-2-ylamino]-phenyl}-benzenesulfonamide;and2,4-difluoro-N-{4-[5-(2-methyl-benzoyl)-thiazol-2-ylamino]-phenyl}-benzenesulfonamide;or a pharmaceutically acceptable salt or ester thereof.
 14. The compoundaccording to claim 1, selected from the group consisting of:2-methyl-N-{4-[5-(2-methyl-benzoyl)-thiazol-2-ylamino]-phenyl}-benzenesulfonamide;2,5-dimethyl-N-{4-[5-(2-methyl-benzoyl)-thiazol-2-ylamino]-phenyl}-benzenesulfonamide;and5-fluoro-2-methyl-N-{4-[5-(2-methyl-benzoyl)-thiazol-2-ylamino]-phenyl}-benzenesulfonamide;or a pharmaceutically acceptable salt thereof.
 15. The compoundaccording to claim 1, selected from the group consisting of:3-methoxy-N-{4-[5-(2-methyl-benzoyl)-thiazol-2-ylamino]-phenyl}-benzenesulfonamide;4-methoxy-N-{4-[5-(2-methyl-benzoyl)-thiazol-2-ylamino]-phenyl}-benzenesulfonamide;and2-methoxy-5-methyl-N-{4-[5-(2-methyl-benzoyl)-thiazol-2-ylamino]-phenyl}-benzenesulfonamide;or a pharmaceutically acceptable salt thereof.
 16. The compoundaccording to claim 1, selected from the group consisting of:2,5-dimethoxy-N-{4-[5-(2-methyl-benzoyl)-thiazol-2-ylamino]-phenyl}-benzenesulfonamide;5-chloro-2-methoxy-N-{4-[5-(2-methyl-benzoyl)-thiazol-2-ylamino]-phenyl}-benzenesulfonamide;N-{4-[5-(2-methyl-benzoyl)-thiazol-2-ylamino]-phenyl}-4-trifluoromethoxy-benzenesulfonamide;N-{4-[5-(2-methyl-benzoyl)-thiazol-2-ylamino]-phenyl}-3-nitro-benzenesulfonamide;2-chloro-N-{4-[5-(2-methyl-benzoyl)-thiazol-2-ylamino]-phenyl}-5-trifluoromethyl-benzenesulfonamide;4-chloro-N-{4-[5-(2-methyl-benzoyl)-thiazol-2-ylamino]-phenyl}-benzenesulfonamide;N-{4-[5-(2-methyl-benzoyl)-thiazol-2-ylamino]-phenyl}-4-nitro-benzenesulfonamide;pyrrolidine-1-sulfonic acid{4-[5-(2-methyl-benzoyl)-thiazol-2-ylamino]-phenyl}-amide;dimethylamine-1-sulfonic acid{4-[5-(2-methyl-benzoyl)-thiazol-2-ylamino]-phenyl}-amide; andthiophene-2-sulfonic acid{3-[5-(2-methyl-benzoyl)-thiazol-2-ylamino]-phenyl}-amide; or apharmaceutically acceptable salt thereof.
 17. The compound according toclaim 1, selected from the group consisting of:5-chloro-thiophene-2-sulfonic acid{3-[5-(2-methyl-benzoyl)-thiazol-2-ylamino]-phenyl}-amide;3-fluoro-N-{3-[5-(2-methyl-benzoyl)-thiazol-2-ylamino]-phenyl}-benzenesulfonamide;4-fluoro-N-{3-[5-(2-methyl-benzoyl)-thiazol-2-ylamino]-phenyl}-benzenesulfonamide;2-methyl-N-{3-[5-(2-methyl-benzoyl)-thiazol-2-ylamino]-phenyl}-benzenesulfonamide;2,5-dimethyl-N-{3-[5-(2-methyl-benzoyl)-thiazol-2-ylamino]-phenyl}-benzenesulfonamide;5-fluoro-2-methyl-N-{3-[5-(2-methyl-benzoyl)-thiazol-2-ylamino]-phenyl}-benzenesulfonamide;3-methoxy-N-{3-[5-(2-methyl-benzoyl)-thiazol-2-ylamino]-phenyl}-benzenesulfonamide;4-methoxy-N-{3-[5-(2-methyl-benzoyl)-thiazol-2-ylamino]-phenyl}-benzenesulfonamide;2-methoxy-5-methyl-N-{3-[5-(2-methyl-benzoyl)-thiazol-2-ylamino]-phenyl}-benzenesulfonamide;and2-chloro-N-{3-[5-(2-methyl-benzoyl)-thiazol-2-ylamino]-phenyl}-4-trifluoromethyl-benzenesulfonamide; or a pharmaceutically acceptable salt thereof. 18.The compound according to claim 1, selected from the group consistingof:4-chloro-N-{3-[5-(2-methyl-benzoyl)-thiazol-2-ylamino]-phenyl}-benzenesulfonamide;N-{3-[5-(2-methyl-benzoyl)-thiazol-2-ylamino]-phenyl}-3-nitro-benzenesulfonamide;dimethylamine-1-sulfonic acid{3-[5-(2-methyl-benzoyl)-thiazol-2-ylamino]-phenyl}-amide;5-fluoro-2-methyl-N-{4-[5-(2-methyl-benzoyl)-thiazol-2-ylamino]-benzyl}-benzenesulfonamide;2,4-difluoro-N-{4-[5-(2-methyl-benzoyl)-thiazol-2-ylamino]-benzyl}-benzenesulfonamide;5-chloro-thiophene-2-sulfonic acid4-[5-(2-methyl-benzoyl)-thiazol-2-ylamino]-benzylamide;5-chloro-2-methoxy-N-{4-[5-(2-methyl-benzoyl)-thiazol-2-ylamino]-benzyl}-benzenesulfonamide;2-chloro-N-{4-[5-(2-methyl-benzoyl)-thiazol-2-ylamino]-benzyl}-4-trifluoromethyl-benzenesulfonamide; thiophene-3-sulfonic acid4-[5-(2-methyl-benzoyl)-thiazol-2-ylamino]-benzylamide; and4-fluoro-N-{4-[5-(2-methyl-benzoyl)-thiazol-2-ylamino]-benzyl}-benzenesulfonamide;or a pharmaceutically acceptable salt thereof.
 19. The compoundaccording to claim 1, selected from the group consisting of:2-fluoro-N-{4-[5-(2-methyl-benzoyl)-thiazol-2-ylamino]-benzyl}-benzenesulfonamide;3-fluoro-N-{4-[5-(2-methyl-benzoyl)-thiazol-2-ylamino]-benzyl}-benzenesulfonamide;2-chloro-N-{4-[5-(2-methyl-benzoyl)-thiazol-2-ylamino]-benzyl}-5-trifluoromethyl-benzenesulfonamide;N-{4-[5-(2-methyl-benzoyl)-thiazol-2-ylamino]-benzyl}-3-nitro-benzenesulfonamide;4-chloro-N-{4-[5-(2-methyl-benzoyl)-thiazol-2-ylamino]-benzyl}-benzenesulfonamide;N-{4-[5-(2-methyl-benzoyl)-thiazol-2-ylamino]-benzyl}-4-nitro-benzenesulfonamide;dimethylamine-1-sulfonic acid4-[5-(2-methyl-benzoyl)-thiazol-2-ylamino]-benzylamide;2-methyl-N-{4-[5-(2-methyl-benzoyl)-thiazol-2-ylamino]-benzyl}-benzenesulfonamide;2,5-dimethyl-N-{4-[5-(2-methyl-benzoyl)-thiazol-2-ylamino]-benzyl}-benzenesulfonamide;and4-methoxy-N-{4-[5-(2-methyl-benzoyl)-thiazol-2-ylamino]-benzyl}-benzenesulfonamide;or a pharmaceutically acceptable salt thereof.
 20. The compoundaccording to claim 1, selected from the group consisting of:3-methoxy-N-{4-[5-(2-methyl-benzoyl)-thiazol-2-ylamino]-benzyl}-benzenesulfonamide;5-fluoro-2-methyl-N-{3-[5-(2-methyl-benzoyl)-thiazol-2-ylamino]-benzyl}-benzenesulfonamide;2,4-difluoro-N-{3-[5-(2-methyl-benzoyl)-thiazol-2-ylamino]-benzyl}-benzenesulfonamide;5-chloro-thiophene-2-sulfonic acid3-[5-(2-methyl-benzoyl)-thiazol-2-ylamino]-benzylamide;5-chloro-2-methoxy-N-{3-[5-(2-methyl-benzoyl)-thiazol-2-ylamino]-benzyl}-benzenesulfonamide;2-chloro-N-{3-[5-(2-methyl-benzoyl)-thiazol-2-ylamino]-benzyl}-4-trifluoromethyl-benzenesulfonamide;2,5-dimethoxy-N-{3-[5-(2-methyl-benzoyl)-thiazol-2-ylamino]-benzyl}-benzenesulfonamide;3-methoxy-N-{3-[5-(2-methyl-benzoyl)-thiazol-2-ylamino]-benzyl}-benzenesulfonamide;2-chloro-N-{3-[5-(2-methyl-benzoyl)-thiazol-2-ylamino]-benzyl}-5-trifluoromethyl-benzenesulfonamide; andN-{3-[5-(2-methyl-benzoyl)-thiazol-2-ylamino]-benzyl}-3-nitro-benzenesulfonamide;or a pharmaceutically acceptable salt thereof.
 21. The compoundaccording to claim 1, selected from the group consisting of:4-chloro-N-{3-[5-(2-methyl-benzoyl)-thiazol-2-ylamino]-benzyl}-benzenesulfonamide;N-{3-[5-(2-methyl-benzoyl)-thiazol-2-ylamino]-benzyl}-4-nitro-benzenesulfonamide;C-(4-fluoro-phenyl)-N-{3-[5-(2-methyl-benzoyl)-thiazol-2-ylamino]-benzyl}-methanesulfonamide;4-methoxy-N-{3-[5-(2-methyl-benzoyl)-thiazol-2-ylamino]-benzyl}-benzenesulfonamide;2,5-dimethyl-N-{3-[5-(2-methyl-benzoyl)-thiazol-2-ylamino]-benzyl}-benzenesulfonamide;pyrrolidine-1-sulfonic acid3-[5-(2-methyl-benzoyl)-thiazol-2-ylamino]-benzylamide;thiophene-2-sulfonic acid3-[5-(2-methyl-benzoyl)-thiazol-2-ylamino]-benzylamide;thiophene-3-sulfonic acid3-[5-(2-methyl-benzoyl)-thiazol-2-ylamino]-benzylamide;2-methyl-N-{3-[5-(2-methyl-benzoyl)-thiazol-2-ylamino]-benzyl}-benzenesulfonamide;2-fluoro-N-{3-[5-(2-methyl-benzoyl)-thiazol-2-ylamino]-benzyl}-benzenesulfonamide;and3-fluoro-N-{3-[5-(2-methyl-benzoyl)-thiazol-2-ylamino]-benzyl}-benzenesulfonamide.or a pharmaceutically acceptable salt thereof.
 22. The compoundaccording to claim l'selected from the group consisting of:thiophene-3-sulfonic acid{4-[5-(2-methyl-benzoyl)-thiazol-2-ylamino]-phenyl}-amide;3-fluoro-N-{4-[5-(2-methyl-benzoyl)-thiazol-2-ylamino]-phenyl}-benzenesulfonamide;and4-fluoro-N-{4-[5-(2-methyl-benzoyl)-thiazol-2-ylamino]-phenyl}-benzenesulfonamide;or a pharmaceutically acceptable salt thereof.
 23. The compoundaccording to claim 1, selected from the group consisting of:2-methyl-N-{4-[5-(2-methyl-benzoyl)-thiazol-2-ylamino]-phenyl}-benzenesulfonamide;2-methoxy-5-methyl-N-{4-[5-(2-methyl-benzoyl)-thiazol-2-ylamino]-phenyl}-benzenesulfonamide;and dimethylamine-1-sulfonic acid{4-[5-(2-methyl-benzoyl)-thiazol-2-ylamino]-phenyl}-amide; or apharmaceutically acceptable salt thereof.
 24. The compound according toclaim 1, selected from the group consisting of: thiophene-2-sulfonicacid {3-[5-(2-methyl-benzoyl)-thiazol-2-ylamino]-phenyl}-amide;5-fluoro-2-methyl-N-{4-[5-(2-methyl-benzoyl)-thiazol-2-ylamino]-benzyl}-benzenesulfonamide;and2,4-difluoro-N-{4-[5-(2-methyl-benzoyl)-thiazol-2-ylamino]-benzyl}-benzenesulfonamide;or a pharmaceutically acceptable salt thereof.
 25. The compoundaccording to claim 1, selected from the group consisting of:5-chloro-2-methoxy-N-{4-[5-(2-methyl-benzoyl)-thiazol-2-ylamino]-benzyl}-benzenesulfonamide;2-fluoro-N-{4-[5-(2-methyl-benzoyl)-thiazol-2-ylamino]-benzyl}-benzenesulfonamide;and3-fluoro-N-{4-[5-(2-methyl-benzoyl)-thiazol-2-ylamino]-benzyl}-benzenesulfonamide;or a pharmaceutically acceptable salt thereof.
 26. The compoundaccording to claim 1, selected from the group consisting of:2-chloro-N-{4-[5-(2-methyl-benzoyl)-thiazol-2-ylamino]-benzyl}-5-trifluoromethyl-benzenesulfonamide;N-{4-[5-(2-methyl-benzoyl)-thiazol-2-ylamino]-benzyl}-3-nitro-benzenesulfonamide;andN-{4-[5-(2-methyl-benzoyl)-thiazol-2-ylamino]-benzyl}-4-nitro-benzenesulfonamide;or a pharmaceutically acceptable salt thereof.
 27. The compoundaccording to claim 1, selected from the group consisting of:dimethylamine-1-sulfonic acid4-[5-(2-methyl-benzoyl)-thiazol-2-ylamino]-benzylamide;2-methyl-N-{4-[5-(2-methyl-benzoyl)-thiazol-2-ylamino]-benzyl}-benzenesulfonamide;and4-methoxy-N-{4-[5-(2-methyl-benzoyl)-thiazol-2-ylamino]-benzyl}-benzenesulfonamide;or a pharmaceutically acceptable salt thereof.
 28. A pharmaceuticalcomposition comprising a compound in accordance with claim 1 or apharmaceutically acceptable salt thereof and a therapeutically inertcarrier.
 29. A method for the treatment of obesity in a patient in needof such treatment, comprising administering a therapeutically effectiveamount of a compound of claim
 1. 30. A method for treatment of obesityin a patient in need of such treatment, comprising administering to thepatient a therapeutically effective amount of a compound of claim 1 anda therapeutically effective amount of orlistat.
 31. The pharmaceuticalcomposition of claim 28 further comprising a therapeutically effectiveamount of a orlistat.